Modulators of sphingosine phosphate receptors

ABSTRACT

Compounds that activate a sphingosine-1-phosphate receptor of the subtype 1 are provided. Certain compounds selectively activate the receptor subtype 1 in relation to the sphinogosine-1-phosphate receptor subtype 3. Uses and methods of inventive compounds for treatment of malconditions wherein activation, agonism, inhibition or antagonism of the S1P1 is medically indicated are provided.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of and claims the benefit of priorityto U.S. patent application Ser. No. 12/465,767, filed May 14, 2009,which application claims the priority of U.S. Ser. No. 61/127,603, filedMay 14, 2008, the disclosure of which are incorporated by referenceherein in their entirety.

STATEMENT OF GOVERNMENT SUPPORT

This invention was made with government support under Grant Nos.MH084512 and MH074404, awarded by the National Institutes of Health. Thegovernment has certain rights in the invention.

BACKGROUND

Sphingosine-1-phosphate (S1P), the structure of which is shown below, isa phospholipid with a wide range of biological activities, notably,involved in cellular signaling.

For example, S1P modulates cellular proliferation, such as of epidermalcells. The bioactivity of S1P is mediated by multiple receptor subtypes.For example, receptors subtypes 1 and 3, (S1P1 and S1P3 respectively)are both expressed in endothelial cells, and play a role in lung andlymphoid endothelial functions. Thus, agonists of receptors, such asagonists of S1P1, could be of value in the treatment of malconditionssuch as multiple sclerosis, transplant rejection, and adult respiratorydistress syndrome. Agonist stimulation of the S1P1 receptor is modulatedby receptor degradation. Ligand stimulation induces receptorphosphorylation, internalization, polyubiquination and degradation(Gonzalez-Cabrera, Hla et al. 2007).

Oxadiazoles and oxazoles have been described for use assphingosine-1-phosphate receptor ligands, see for examples PCT patentapplication publication numbers WO2006/131336, WO2008/037476 andWO2008074821.

SUMMARY

The present invention is directed to heterocyclic compounds adapted toact as agonists of SIP receptor subtype 1, S1P1; methods of preparationand methods of use, such as in treatment of a malcondition mediated byS1P1 activation, or when activation of S1P1 is medically indicated.

Accordingly, various embodiments of the present invention provide acompound of formula (I) or a pharmaceutically acceptable salt, prodrug,tautomer, stereoisomer, hydrate, or solvate thereof:

wherein

a dashed line signifies that a single bond or a double bond can bepresent, provided that there are two double bonds and three single bondsin the ring comprising A¹, A², and A³;

A¹, A², and A³ each independently is C or O or is N when the N is bondedto two adjacent ring atoms by a double bond and a single bond or is NRwherein R is H or (C₁-C₆)alkyl when the N is bonded to two adjacent ringatoms by two single bonds; provided that no more than one of A¹, A², andA³ is C and that at least one of A¹, A², and A³ is N or NR; providedthat only one of A¹, A², and A³ is O;

L¹ and L² are each independently a bond; (CHR′)_(n) wherein R′ is H or(C₁-C₆)alkyl and n is 1, 2, or 3; or a heteroaryl selected from thegroup consisting of thiophenyl, phenyl, furanyl, or benzothiophenyl andwherein such heteroaryl is substituted with 0-3 J;

J independently at each occurrence is F, Cl, Br, I, OR′, OC(O)N(R′)₂,CN, CF₃, OCF₃, CHF₂, NO₂, R′, O, S, C(O), S(O), methylenedioxy,ethylenedioxy, N(R′)₂, N(R′)CH₂CH₂OR′, SR′, SOR′, SO₂R′, SO₂N(R′)₂,SO₃R′, C(O)R′, C(O)C(O)R′, C(O)CH₂C(O)R′, C(S)R′, C(O)OR′, OC(O)R′,OC(O)OR′, C(O)N(R′)₂, OC(O)N(R′)₂, C(S)N(R′)₂, (CH₂)₀₋₂NHC(O)R′,(CH₂)₀₋₂N(R′)₂, (CH₂)₀₋₂N(R′)N(R′)₂, N(R′)N(R′)C(O)R′,N(R′)N(R′)C(O)OR′, N(R′)N(R′)CON(R′)₂, N(R′)SO₂R′, N(R′)SO₂N(R′)₂,N(R′)C(O)OR′, N(R′)C(O)R′, N(R′)N(R′), N(R′)C(S)R′, N(R′)C(O)N(R′)₂,N(R)C(S)N(R′)₂, N(COR′)COR′, N(OR′)R′, C(═NH)N(R′)₂, C(O)N(OR′)R′, orC(═NOR′)R′, wherein two J groups together can form a ring; wherein R′ isindependently at each occurrence hydrogen or an alkyl, cycloalkyl, aryl,heterocyclyl, or heteroaryl wherein any alkyl, cycloalkyl, aryl,heterocyclyl or heteroaryl is substituted with 0-3 J; or wherein two R′groups together with a nitrogen atom or with two adjacent nitrogen atomsto which they are bonded can together form a (C₃-C₈)heterocyclylsubstituted with 0-3 J; optionally further comprising 1-3 additionalheteroatoms selected from the group consisting of O, N, S, S(O) andS(O)₂;

R⁵ is a mono- or bicyclic cycloalkyl, aryl, heterocyclyl, or heteroaryl;each of which is substituted with 0-5 J, wherein any cycloalkyl, aryl,heterocyclyl, or heteroaryl can be fused, bridged, or in a spiroconfiguration with one or more additional cycloalkyl, aryl,heterocyclyl, heteroaryl rings, any of which can be monocyclic, bicyclicor polycyclic, saturated, partially unsaturated, or aromatic, and any ofwhich is substituted with 0-5 J;

R⁶ is cycloalkyl, aryl, heterocyclyl, or heteroaryl, wherein anycycloalkyl, aryl, heterocyclyl, or heteroaryl is independently mono- orpluri-substituted with J, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,(C₁-C₆)haloalkyl, hydroxyl, halo, (C₁-C₆)haloalkoxy,cycloalkyl(C₁-C₆)alkyl, heterocyclyl(C₁-C₆)alkyl, aryl(C₁-C₆)alkyl,heteroaryl(C₁-C₆)alkyl, OR³ wherein R³ comprises H or (C₁-C₆)alkyl orNR⁴ ₂ wherein each R⁴ independently comprises H or (C₁-C₆)alkyl or wheretwo R⁴ groups together with a nitrogen atom to which they are bondedform a (C₃-C₈)heterocyclyl which optionally further comprises 1-3heteroatoms selected from the group consisting of N, O, S, S(O) andS(O)₂; or R⁴ is optionally substituted cycloalkyl, optionallysubstituted aryl, optionally substituted heterocyclyl, or optionallysubstituted heteroaryl;

wherein any alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, R³,R⁴, cycloalkyl, aryl, heterocyclyl, or heteroaryl can be furthersubstituted with J;

and

provided that (i), (ii), (iii) or (iv) applies:

(i) L¹ is bond or (CHR′)_(n) and R⁵ is a bicyclic ring moiety which isoptionally substituted with 0-5 J where the bicyclic ring moiety is anyone of a-i to a-xxviii wherein a wavy line indicates a point ofattachment:

provided that when R⁵ is either a-xvii or a-xix that L² is bond or(CHR′)_(n);

(ii) L¹ and L² are each independently a bond or (CHR′)_(n); R⁵ is a6-membered heteroaryl ring moiety optionally substituted with 0-3 J¹,wherein J¹ is OR′, CF₃, Cl, Br, F, CN, O(C₁-C₆)alkoxy,O(C₁-C₆)cycloalkoxy, alkyl, or N(R′)₂ and wherein the 6-memberedheteroaryl ring moiety is any one of b-i to b-xiii wherein a wavy lineindicates a point of attachment:

(iii) L¹ is a bond or (CHR′)_(n), and L² is a heteroaryl substitutedwith 0-3 J wherein the heteroaryl is c-i or c-ii wherein a wavy lineindicates a point of attachment:

or

(iv) L¹ is a bond or (CHR′)_(n) and L² is a bond or (CHR′)_(n) or aphenyl substituted with 0-5 J; and R⁵ and R⁶ are independently selectedfrom phenyl or heteroaryl each optionally substituted with 0-5occurrences of J; provided that if L² is a bond and R⁵ and R⁶ are bothphenyl, then R⁵ is substituted with at least one of 4-CN, 3-alkyl-NHR′,3-alkyl-OR′, 4-alkyl-OR′, or 2,3-dialkyl and R⁶ is substituted with atleast 4-OR′; provided, that when (ii), (iii), or (iv) applies, that thecompound of formula (I) is not one of the following:

In various embodiments, a pharmaceutical composition comprising acompound of the invention and a suitable excipient is provided.

In various combinations a pharmaceutical combination comprising acompound of the invention and a second medicament is provided. Invarious embodiments the second medicament is medically indicated for thetreatment of multiple sclerosis, transplant rejection, or adultrespiratory distress syndrome.

Various embodiments of the invention provide a method of activation,agonism, inhibition, or antagonism of a sphingosine-1-phosphate receptorsubtype 1 comprising contacting the receptor subtype 1 with an effectiveamount of a compound of formula (II) or a pharmaceutically acceptablesalt, prodrug, tautomer, stereoisomer, hydrate, or solvate thereof:

wherein

a dashed line signifies that a single bond or a double bond can bepresent, provided that there are two double bonds and three single bondsin the ring comprising A¹, A², and A³;

A¹, A², and A³ each independently is C or O or is N when the N is bondedto two adjacent ring atoms by a double bond and a single bond or is NRwherein R is H or (C₁-C₆)alkyl when the N is bonded to two adjacent ringatoms by two single bonds; provided that no more than one of A¹, A², andA³ is C and that at least one of A¹, A², and A³ is N or NR; providedthat only one of A¹, A², and A³ is O;

L¹ and L² are each independently a bond; (CHR′)_(n) wherein R′ is H or(C₁-C₆)alkyl and n is 1, 2, or 3; or a heteroaryl selected from thegroup consisting of thiophenyl, phenyl, furanyl, or benzothiophenyl andwherein such heteroaryl is substituted with 0-3 J;

J independently at each occurrence is F, Cl, Br, I, OR′, OC(O)N(R′)₂,CN, CF₃, OCF₃, CHF₂, NO₂, R′, O, S, C(O), S(O), methylenedioxy,ethylenedioxy, N(R′)₂, N(R′)CH₂CH₂OR′, SR′, SOR′, SO₂R′, SO₂N(R′)₂,SO₃R′, C(O)R′, C(O)C(O)R′, C(O)CH₂C(O)R′, C(S)R′, C(O)OR′, OC(O)R′,OC(O)OR′, C(O)N(R′)₂, OC(O)N(R′)₂, C(S)N(R′)₂, (CH₂)₀₋₂NHC(O)R′,(CH₂)₀₋₂N(R′)₂, (CH₂)₀₋₂N(R′)N(R′)₂, N(R′)N(R′)C(O)R′,N(R′)N(R′)C(O)OR′, N(R′)N(R′)CON(R′)₂, N(R′)SO₂R′, N(R′)SO₂N(R′)₂,N(R′)C(O)OR′, N(R′)C(O)R′, N(R′)N(R′), N(R′)C(S)R′, N(R′)C(O)N(R′)₂,N(R′)C(S)N(R′)₂, N(COR′)COR′, N(OR′)R′, C(═NH)N(R′)₂, C(O)N(OR′)R′, orC(═NOR′)R′, wherein two J groups together can form a ring; wherein R′ isindependently at each occurrence hydrogen or an alkyl, cycloalkyl, aryl,heterocyclyl, or heteroaryl wherein any alkyl, cycloalkyl, aryl,heterocyclyl or heteroaryl is substituted with 0-3 J; or wherein two R′groups together with a nitrogen atom or with two adjacent nitrogen atomsto which they are bonded can together form a (C₃-C₈)heterocyclylsubstituted with 0-3 J; optionally further comprising 1-3 additionalheteroatoms selected from the group consisting of O, N, S, S(O) andS(O)₂;

R⁵ is a mono- or bicyclic cycloalkyl, aryl, heterocyclyl, or heteroaryl;each of which is substituted with 0-5 J, wherein any cycloalkyl, aryl,heterocyclyl, or heteroaryl can be fused, bridged, or in a spiroconfiguration with one or more additional cycloalkyl, aryl,heterocyclyl, heteroaryl rings, any of which can be monocyclic, bicyclicor polycyclic, saturated, partially unsaturated, or aromatic, and any ofwhich is substituted with 0-5 J;

R⁶ is cycloalkyl, aryl, heterocyclyl, or heteroaryl, wherein anycycloalkyl, aryl, heterocyclyl, or heteroaryl is independently mono- orpluri-substituted with J, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,(C₁-C₆)haloalkyl, hydroxyl, halo, (C₁-C₆)haloalkoxy,cycloalkyl(C₁-C₆)alkyl, heterocyclyl(C₁-C₆)alkyl, aryl(C₁-C₆)alkyl,heteroaryl(C₁-C₆)alkyl, OR³ wherein R³ comprises H or (C₁-C₆)alkyl orNR⁴ ₂ wherein each R⁴ independently comprises H or (C₁-C₆)alkyl or wheretwo R⁴ groups together with a nitrogen atom to which they are bondedform a (C₃-C₈)heterocyclyl which optionally further comprises 1-3heteroatoms selected from the group consisting of N, O, S, S(O) andS(O)₂; or R⁴ is optionally substituted cycloalkyl, optionallysubstituted aryl, optionally substituted heterocyclyl, or optionallysubstituted heteroaryl;

wherein any alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, R³,R⁴, cycloalkyl, aryl, heterocyclyl, or heteroaryl can be furthersubstituted with J;

and

provided that (i), (ii), (iii) or (iv) applies:

(i) L¹ is bond or (CHR′)_(n) and R⁵ is a bicyclic ring moiety which isoptionally substituted with 0-5 J where the bicyclic ring moiety is anyone of a-i to a-xxviii wherein a wavy line indicates a point ofattachment:

provided that when R⁵ is either a-xvii or a-xix that L² is bond or(CHR′)_(n);

(ii) L¹ and L² are each independently a bond or (CHR′)_(n); R⁵ is a6-membered heteroaryl ring moiety optionally substituted with 0-3 J¹,wherein J¹ is OR′, CF₃, Cl, Br, F, CN, O(C₁-C₆)alkoxy,O(C₁-C₆)cycloalkoxy, alkyl, or N(R′)₂ and wherein the 6-memberedheteroaryl ring moiety is any one of b-i to b-xiii wherein a wavy lineindicates a point of attachment:

(iii) L¹ is a bond or (CHR′)_(n), and L² is a heteroaryl substitutedwith 0-3 J wherein the heteroaryl is c-i or c-ii wherein a wavy lineindicates a point of attachment:

or

(iv) L¹ is a bond or (CHR′)_(n) and L² is a bond or (CHR′)_(n) or aphenyl substituted with 0-5 J; and R⁵ and R⁶ are independently selectedfrom phenyl or heteroaryl each optionally substituted with 0-5occurrences of J; provided that if L² is a bond and R⁵ and R⁶ are bothphenyl, then R⁵ is substituted with at least one of 4-CN, 3-alkyl-NHR′,3-alkyl-OR′, 4-alkyl-OR′, or 2,3-dialkyl and R⁶ is substituted with atleast 4-OR′;

provided, that when (ii), (iii), or (iv) applies, that the compound offormula (I) is not one of the following:

In various embodiments, the above compound activates or agonizes, orinhibits or antagonizes, the sphingosine-1-phosphate receptor subtype 1to a greater degree than the compound activates or agonizes, or inhibitsor antagonizes, another subtype of sphingosine-1-phosphate receptor, forexample a sphingosin-1-phosphate receptor subtype 3.

In various embodiments a method of treatment of a malcondition in apatient for which activation or agonism or inhibition or antagonism ofan S1P1 receptor is medically indicated, is provided, comprisingadministering an effective amount of a compound as shown above to thepatient to provide a beneficial effect.

In various embodiment, selective activation or agonism of an S1P1receptor, such as with respect to an S1P3 receptor, is medicallyindicated. In various embodiments, the malcondition comprises multiplesclerosis, transplant rejection, or adult respiratory distress syndrome.In various embodiments, selective inhibition or antagonism of an S1P1receptor is medically indicated, for example, with respect to an S1P3receptor.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the results of a bioassay, as described in the Examples,for S1P1 activation, involving detection of the ubiquination that is aconsequence of S1P1 activation. HEK 293-S1P1-GFP cell lysates wereimmunoprecipitated (IP) and immunoblotted (TB) with P4D1 (antiubiquitin) antibodies to detect S1P1-ubiquination. FIG. 1A showsS1P1-GFP ubiquination was detected as a band running between 64 and 82kDa (lane 1 vehicle control, lane 2 0.5 uM AFD-R, Lane 2 vehicle controlfor SR-917, lane 4 1 uM SR917). FIG. 1B shows Cellular localization ofS1P1-GFP with Veh (vehicle control, 0.01, 0.1 and 1 uM of SR-917. FIG.1C shows S1P1-GFP cells were labeled with P32 and stimulated withagonist. S1P1-GFP was immunoprecipitated, resolved by PAGE, transferredto nitrocellulose and exposed to Kodak XAR film overnight. Lane 1Vehicle control, Lanes 2 and 3, S1P at 0.5 and 0.05 uM, lanes 4 and 5,AFD-R at 0.5 and 0.05 uM, Lanes 6 and 7 SR-917 at 10 and 1 uM. SR-917 isa known agonist of the S1P1 receptor, indexed in the NIH MolecularLibraries Small Molecule Repository (MLMSR). Compound ID is 976135. Itis commercially available from ChemBridge Screening Library.

FIG. 2 shows compound 32 robustly induces internalization andpolyubiquination, and these effects are blocked by the S1P1 antagonist,W146R.

FIG. 3 shows that compound 236, like other compounds in the series,induces S1P1 polyubiquination.

FIG. 4 shows compound 236 induces lymphopenia in mice. The compound wasdissolved in 10% DMSO, Tween-20 and delivered by gavage. FIG. 4A showscomparisons of the effects of compound CYM-5442 (236) in CD4, CD8, B220,and CD11b mouse lines, with respect to the percent leucocytes of totalcells versus no treatment, vehicle, and control SEW2897. FIG. 4B showscomparisons of the effects of compound CYM-5442 (236) in CD4, CD8, B220mouse lines with respect to the percent leucocytes of total cells versusvehicle, and control SEW2897.

FIG. 5 shows a pharmacokinetic study of SR-917 1 mg/mL in 10/10/80DMSO/Tween/Water delivered 1 mg/kg i.v.

FIG. 6 shows S1P1 Polar Ligand Binding Pocket Mutations. CHO cells weretransfected with S1P1 cDNA constructs. Cells were serum starvedovernight and stimulated with 3-fold serial dilutions of SIP orCYM-5442. ERK1/2 phosphorylation was detected with the Phospho-ERK ELISA(Cell Signaling). FIG. 6A shows S1P1 mutants E121A and R292A. FIG. 6Bshows wild type S1P1 (wt) and S1P1 mutants R120A.

DETAILED DESCRIPTION

As used in the specification and the appended claims, the singular forms“a,” “an” and “the” include plural referents unless the context clearlydictates otherwise.

As used herein, “individual” (as in the subject of the treatment) meansboth mammals and non-mammals. Mammals include, for example, humans;non-human primates, e.g. apes and monkeys; cattle; horses; sheep; andgoats. Non-mammals include, for example, fish and birds.

The term “S1P1” as used herein refers to subtype 1 of asphingosine-1-phosphate receptor, while other sphingosine-1-phosphatereceptor subtypes are referred to in a corresponding manner, forexample, sphingosine-1-phosphate receptor subtype 3 is referred to as“S1P3”.

A “receptor”, as is well known in the art, is a biomolecular entityusually comprising a protein that specifically binds a structural classof ligands or a single native ligand in a living organism, the bindingof which causes the receptor to transduce the binding signal intoanother kind of biological action, such as signaling a cell that abinding event has occurred, which causes the cell to alter its functionin some manner. An example of transduction is receptor binding of aligand causing alteration of the activity of a “G-protein” in thecytoplasm of a living cell that is coupled with the receptor. Anymolecule, naturally occurring or not, that binds to a receptor andactivates it for signal transduction, is referred to as an “agonist” or“activator.” Any molecule, naturally occurring or not, that binds to areceptor, but does not cause signal transduction to occur, and which canblock the binding of an agonist and its consequent signal transduction,is referred to as an “antagonist.”

An “S1P1 compound” or “S1P1 agonist” or “S1P1 activator” or “S1P1inhibitor” or “S1P1 antagonist” as the terms are used herein refer tocompounds that interact in some way with the S1P receptor subtype 1.They can be agonist or activators, or they can be antagonists orinhibitors. An “S1P1 compound” of the invention can be selective foraction on subtype 1 of the S1P receptor family; for example a compoundof the invention can act at a lower concentration on subtype 1 of theS1P receptor family than on other subtypes of the S1P receptor family;more specifically, an “S1P1 compound” of the invention can selectivelyact on subtype 1 receptors compared to its action on subtype 3, or“S1P3” receptors.

In certain embodiments, compounds of the invention are orthostaticagonists. In certain other embodiments, compounds of the invention areallosteric agonists. Receptor agonists may be classified as orthostericor allosteric. An orthosteric agonist binds to a site in the receptorthat significantly overlaps with the binding of the natural ligand andreplicates the key interactions of the natural ligand with the receptor.An orthosteric agonist will activate the receptor by a molecularmechanism similar to that of the natural ligand, will be competitive forthe natural ligand, and will be competitively antagonized bypharmacological agents that are competitive antagonists for the naturalligand. An allosteric agonist binds to a site in the receptor that makessome significant interactions that are partly or wholly non-overlappingwith the natural ligand. Allosteric agonists are true agonists and notallosteric potentiators. Consequently, they activate receptor signalingalone and without a requirement for a sub-maximal concentration of thenatural ligand. Allosteric agonists may be identified when an antagonistknown to be competitive for the orthosteric ligand shows non-competitiveantagonism. The allosteric agonist site can also be mapped by receptormutagenesis. The introduction of single point mutations in receptorsthat retain receptor activation by allosteric agonist, while diminishingor abolishing signaling induced by orthosteric agonist or vice versaprovide formal evidence for differences in binding interactions.Orthosteric agonists may destabilize GPCR (“G-protein coupled receptor”)structure and conformation, while allosteric agonists may eitherstabilize or destabilize GPCR structure and conformation. Allostericagonists, by virtue of their different interactions with receptor, maybe pharmaceutically useful because the allosteric site may conferadditional opportunities for agonist potency and selectivity within arelated family of receptor subtypes that share a similar orthostericligand. In addition, the allosteric site may require very differentphysical and chemical properties of an agonist compared to theorthosteric ligand. These chemico-physical properties, which includehydrophobicity, aromaticity, charge distribution and solubility may alsoprovide advantages in generating agonists of varying pharmacokinetic,oral bioavailability, distributional and metabolism profiles thatfacilitate the development of effective pharmaceutical substances.

“Substantially” as the term is used herein means completely or almostcompletely; for example, a composition that is “substantially free” of acomponent either has none of the component or contains such a traceamount that any relevant functional property of the composition isunaffected by the presence of the trace amount; or a compound that is“substantially pure” has only negligible traces of impurities present.

“Treating” or “treatment” within the meaning herein refers to analleviation of symptoms associated with a disorder, malcondition, ordisease, or inhibition of further progression or worsening of thosesymptoms, or prevention or prophylaxis of the disorder, malcondition, ordisease.

The expression “effective amount”, when used to describe use of acompound of the invention in providing therapy to a patient sufferingfrom a disorder or malcondition mediated by a sphingosine-1-phospatereceptor of subtype 1 refers to the amount of a compound of theinvention that is effective to bind as an agonist or as an antagonist toan S1P1 receptor in the individual's tissues, wherein the S1P1 receptoris implicated in the disorder, wherein such binding occurs to an extentsufficient to produce a beneficial therapeutic effect on the patient.Similarly, as used herein, an “effective amount” or a “therapeuticallyeffective amount” of a compound of the invention refers to an amount ofthe compound that alleviates, in whole or in part, symptoms associatedwith the disorder or malcondition, or halts or slows further progressionor worsening of those symptoms, or prevents or provides prophylaxis forthe disorder or malcondition. In particular, a “therapeuticallyeffective amount” refers to an amount effective, at dosages and forperiods of time necessary, to achieve the desired therapeutic result byacting as an agonist or activator of sphingosine-1-phosphate receptorsubtype 1 (S1P1) activity. A therapeutically effective amount is alsoone in which any toxic or detrimental effects of compounds of theinvention are outweighed by the therapeutically beneficial effects. Forexample, in the context of treating a malcondition mediated byactivation of S1P1, a therapeutically effective amount of an S1P1agonist of the invention is an amount sufficient to control themalcondition, to mitigate the progress of the malcondition, or torelieve the symptoms of the malcondition. Examples of malconditions thatcan be so treated include multiple sclerosis, transplant rejection, andadult respiratory distress syndrome.

All chiral, diastereomeric, racemic forms of a structure are intended,unless a particular stereochemistry or isomeric form is specificallyindicated. Compounds used in the present invention can include enrichedor resolved optical isomers at any or all asymmetric atoms as areapparent from the depictions, at any degree of enrichment. Both racemicand diastereomeric mixtures, as well as the individual optical isomerscan be isolated or synthesized so as to be substantially free of theirenantiomeric or diastereomeric partners, and these are all within thescope of the invention.

Isomerism and Tautomerism in Compounds of the Invention

Tautomerism

Within the present invention it is to be understood that a compound ofthe formula I or a salt thereof may exhibit the phenomenon oftautomerism whereby two chemical compounds that are capable of facileinterconversion by exchanging a hydrogen atom between two atoms, toeither of which it forms a covalent bond. Since the tautomeric compoundsexist in mobile equilibrium with each other they may be regarded asdifferent isomeric forms of the same compound. It is to be understoodthat the formula drawings within this specification can represent onlyone of the possible tautomeric forms. However, it is also to beunderstood that the invention encompasses any tautomeric form which actson S1P receptors, such as S1P subtype 1 receptors, and is not to belimited merely to any one tautomeric form utilized within the formulaedrawings. The formula drawings within this specification can representonly one of the possible tautomeric forms and it is to be understoodthat the specification encompasses all possible tautomeric forms of thecompounds drawn not just those forms which it has been convenient toshow graphically herein. For example, tautomerism may be exhibited by apyrazolyl group bonded as indicated by the wavy line. While bothsubstituents would be termed a 4-pyrazolyl group, it is evident that adifferent nitrogen atom bears the hydrogen atom in each structure.

Such tautomerism can also occur with substituted pyrazoles such as3-methyl, 5-methyl, or 3,5-dimethylpyrazoles, and the like.

Optical Isomerism

It will be understood that when compounds of the present inventioncontain one or more chiral centers, the compounds may exist in, and maybe isolated as pure enantiomeric or diastereomeric forms or as racemicmixtures. The present invention therefore includes any possibleenantiomers, diastereomers, racemates or mixtures thereof of thecompounds of the invention which are biologically active in thetreatment of S1P1 mediated diseases.

The isomers resulting from the presence of a chiral center comprise apair of non-superimposable isomers that are called “enantiomers.” Singleenantiomers of a pure compound are optically active, i.e., they arecapable of rotating the plane of plane polarized light. Singleenantiomers are designated according to the Cahn-Ingold-Prelog system.Once the priority ranking of the four groups is determined, the moleculeis oriented so that the lowest ranking group is pointed away from theviewer. Then, if the descending rank order of the other groups proceedsclockwise, the molecule is designated (R) and if the descending rank ofthe other groups proceeds counterclockwise, the molecule is designated(S). In the example in Scheme 14, the Cahn-Ingold-Prelog ranking isA>B>C>D. The lowest ranking atom, D is oriented away from the viewer.

The present invention is meant to encompass diastereomers as well astheir racemic and resolved, diastereomerically and enantiomerically pureforms and salts thereof. Diastereomeric pairs may be resolved by knownseparation techniques including normal and reverse phase chromatography,and crystallization.

“Isolated optical isomer” or “isolated enantiomer” means a compoundwhich has been substantially purified from the corresponding opticalisomer (enantiomer) of the same formula. Preferably, the isolated isomeris at least about 80% pure, more preferably at least 90% pure, even morepreferably at least 98% pure, most preferably at least about 99% pure,by weight.

Isolated optical isomers may be purified from racemic mixtures bywell-known chiral separation techniques. According to one such method, aracemic mixture of a compound of the invention, or a chiral intermediatethereof, is separated into 99% wt. % pure optical isomers by HPLC usinga suitable chiral column, such as a member of the series of DAICEL®CHIRALPAK® family of columns (Daicel Chemical Industries, Ltd., Tokyo,Japan). The column is operated according to the manufacturer'sinstructions.

Rotational Isomerism

It is understood that due to chemical properties (i.e., resonancelending some double bond character to the C—N bond) of restrictedrotation about the amide bond linkage (as illustrated below), amongother types of bonds, it is possible to observe separate rotamer speciesand even, under some circumstances, to isolate such species, exampleshown below. It is further understood that certain structural elements,including steric bulk or substituents on the amide nitrogen, may enhancethe stability of a rotamer to the extent that a compound may be isolatedas, and exist indefinitely, as a single stable rotamer. The presentinvention therefore includes any possible stable rotamers of compoundsof the invention which are biologically active in the treatment ofcancer or other proliferative disease states.

D. Regioisomerism

The preferred compounds of the present invention have a particularspatial arrangement of substituents on the aromatic rings, which isrelated to the structure activity relationship demonstrated by thecompound class. Often such substitution arrangement is denoted by anumbering system; however, numbering systems are often not consistentbetween different ring systems. In six-membered aromatic systems, thespatial arrangements are specified by the common nomenclature “para” for1,4-substitution, “meta” for 1,3-substitution and “ortho” for1,2-substitution as shown below.

The compounds of the invention may contain one or more stereogenic(chiral) or asymmetric centers, such as one or more asymmetric carbonatoms. Substituents at a double bond may be present in cis-(“Z”) ortrans (“E”) form unless indicated otherwise. Substituents on a ring canlikewise be disposed cis or trans to each other, or a mixture thereof.The compounds of the invention may thus be present as mixtures ofstereoisomers or preferably as substantially pure stereoisomers. Purestereoisomers may be obtained by separating stereoisomer mixtures or bystereoselective or stereospecific syntheses in manners known to thoseskilled in the art.

All structures encompassed within a claim are “chemically feasible”, bywhich is meant that the structure depicted by any combination orsubcombination of optional substituents meant to be recited by the claimis physically capable of existence with at least some stability as canbe determined by the laws of structural chemistry and byexperimentation. Structures that are not chemically feasible are notwithin a claimed set of compounds.

When a substituent is specified to be an atom or atoms of specifiedidentity, “or a bond”, a configuration is referred to when thesubstituent is “a bond” that the groups that are immediately adjacent tothe specified substituent are directly connected to each other by achemically feasible bonding configuration.

In general, “substituted” refers to an organic group as defined hereinin which one or more bonds to a hydrogen atom contained therein arereplaced by one or more bonds to a non-hydrogen atom such as, but notlimited to, a halogen (i.e., F, Cl, Br, and I); an oxygen atom in groupssuch as hydroxyl groups, alkoxy groups, aryloxy groups, aralkyloxygroups, oxo(carbonyl) groups, carboxyl groups including carboxylicacids, carboxylates, and carboyxlate esters; a sulfur atom in groupssuch as thiol groups, alkyl and aryl sulfide groups, sulfoxide groups,sulfone groups, sulfonyl groups, and sulfonamide groups; a nitrogen atomin groups such as amines, hydroxylamines, nitriles, nitro groups,N-oxides, hydrazides, azides, and enamines; and other heteroatoms invarious other groups. Non-limiting examples of substituents that can bebonded to a substituted carbon (or other) atom include F, Cl, Br, I,OR′, OC(O)N(R′)₂, CN, CF₃, OCF₃, R′, O, S, C(O), S(O), methylenedioxy,ethylenedioxy, N(R′)₂, SR′, SOR′, SO₂R′, SO₂N(R′)₂, SO₃R′, C(O)R′,C(O)C(O)R′, C(O)CH₂C(O)R′, C(S)R′, C(O)OR′, OC(O)R′, C(O)N(R′)₂,OC(O)N(R′)₂, C(S)N(R′)₂, (CH₂)₀₋₂NHC(O)R′, (CH₂)₀₋₂N(R′)N(R′)₂,N(R′)N(R′)C(O)R′, N(R′)N(R′)C(O)OR′, N(R′)N(R′)CON(R′)₂, N(R′)SO₂R′,N(R′)SO₂N(R′)₂, N(R′)C(O)OR′, N(R′)C(O)R′, N(R′)C(S)R′, N(R′)C(O)N(R′)₂,N(R′)C(S)N(R′)₂, N(COR′)COR′, N(OR′)R′, C(═NH)N(R′)₂, C(O)N(OR′)R′, orC(═NOR′)R′ wherein R′ can be hydrogen or a carbon-based moiety, andwherein the carbon-based moiety can itself be further substituted.

Substituted alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl groupsas well as other substituted groups also include groups in which one ormore bonds to a hydrogen atom are replaced by one or more bonds,including double or triple bonds, to a carbon atom, or to a heteroatomsuch as, but not limited to, oxygen in carbonyl (oxo), carboxyl, ester,amide, imide, urethane, and urea groups; and nitrogen in imines,hydroxyimines, oximes, hydrazones, amidines, guanidines, and nitriles.

Substituted ring groups such as substituted aryl, heterocyclyl andheteroaryl groups also include rings and fused ring systems in which abond to a hydrogen atom is replaced with a bond to a carbon atom.Therefore, substituted aryl, heterocyclyl and heteroaryl groups can alsobe substituted with alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, andalkynyl groups as defined herein, which can themselves be furthersubstituted.

The term “heteroatoms” as used herein refers to non-carbon andnon-hydrogen atoms, capable of forming covalent bonds with carbon, andis not otherwise limited. Typical heteroatoms are N, O, and S. Whensulfur (S) is referred to, it is understood that the sulfur can be inany of the oxidation states in which it is found, thus includingsulfoxides (R—S(O)—R′) and sulfones (R—S(O)₂—R′), unless the oxidationstate is specified; thus, the term “sulfone” encompasses only thesulfone form of sulfur; the term “sulfide” encompasses only the sulfide(R—S—R′) form of sulfur. When the phrases such as “heteroatoms selectedfrom the group consisting of O, NH, NR′ and S,” or “[variable] is O, S .. . ” are used, they are understood to encompass all of the sulfide,sulfoxide and sulfone oxidation states of sulfur.

Alkyl groups include straight chain and branched alkyl groups andcycloalkyl groups having from 1 to about 20 carbon atoms, and typicallyfrom 1 to 12 carbons or, in some embodiments, from 1 to 8 carbon atoms.Examples of straight chain alkyl groups include those with from 1 to 8carbon atoms such as methyl, ethyl, n-propyl, n-butyl, n-pentyl,n-hexyl, n-heptyl, and n-octyl groups. Examples of branched alkyl groupsinclude, but are not limited to, isopropyl, iso-butyl, sec-butyl,t-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl groups.Representative substituted alkyl groups can be substituted one or moretimes with any of the groups listed above, for example, amino, hydroxy,cyano, carboxy, nitro, thio, alkoxy, and halogen groups.

Cycloalkyl groups are alkyl groups forming a ring structure, which canbe substituted or unsubstituted. Examples of cycloalkyl include, but arenot limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, and cyclooctyl groups. In some embodiments, the cycloalkylgroup has 3 to 8 ring members, whereas in other embodiments the numberof ring carbon atoms range from 3 to 5, 3 to 6, or 3 to 7. Cycloalkylgroups further include polycyclic cycloalkyl groups such as, but notlimited to, norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, andcarenyl groups, and fused rings such as, but not limited to, decalinyl,and the like. Cycloalkyl groups also include rings that are substitutedwith straight or branched chain alkyl groups as defined above.Representative substituted cycloalkyl groups can be mono-substituted orsubstituted more than once, such as, but not limited to, 2,2-, 2,3-,2,4-2,5- or 2,6-disubstituted cyclohexyl groups or mono-, di- ortri-substituted norbornyl or cycloheptyl groups, which can besubstituted with, for example, amino, hydroxy, cyano, carboxy, nitro,thio, alkoxy, and halogen groups.

The terms “carbocyclic” and “carbocycle” denote a ring structure whereinthe atoms of the ring are carbon. In some embodiments, the carbocyclehas 3 to 8 ring members, whereas in other embodiments the number of ringcarbon atoms is 4, 5, 6, or 7. Unless specifically indicated to thecontrary, the carbocyclic ring can be substituted with as many as Nsubstituents wherein N is the size of the carbocyclic ring with forexample, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, andhalogen groups.

(Cycloalkyl)alkyl groups, also denoted cycloalkylalkyl, are alkyl groupsas defined above in which a hydrogen or carbon bond of the alkyl groupis replaced with a bond to a cycloalkyl group as defined above.

Alkenyl groups include straight and branched chain and cyclic alkylgroups as defined above, except that at least one double bond existsbetween two carbon atoms. Thus, alkenyl groups have from 2 to about 20carbon atoms, and typically from 2 to 12 carbons or, in someembodiments, from 2 to 8 carbon atoms. Examples include, but are notlimited to —CH═CH(CH3), —CH═C(CH3)2, —C(CH3)=CH2, —C(CH3)═CH(CH3),—C(CH2CH3)=CH2, vinyl, cyclohexenyl, cyclopentenyl, cyclohexadienyl,butadienyl, pentadienyl, and hexadienyl among others.

The term “cycloalkenyl” alone or in combination denotes a cyclic alkenylgroup wherein at least one double bond is present in the ring structure.Cycloalkenyl groups include cycloalkyl groups having at least one doublebond between two adjacent carbon atoms. Thus for example, cycloalkenylgroups include but are not limited to cyclohexenyl, cyclopentenyl, andcyclohexadienyl groups.

(Cycloalkenyl)alkyl groups are alkyl groups as defined above in which ahydrogen or carbon bond of the alkyl group is replaced with a bond to acycloalkenyl group as defined above.

Alkynyl groups include straight and branched chain alkyl groups, exceptthat at least one triple bond exists between two carbon atoms. Thus,alkynyl groups have from 2 to about 20 carbon atoms, and typically from2 to 12 carbons or, in some embodiments, from 2 to 8 carbon atoms.Examples include, but are not limited to —C≡CH, —C≡C(CH₃), —C≡C(CH₂CH₃),—CH₂C≡CH, —CH₂C≡C(CH₃), and —CH₂C≡C(CH₂CH₃), among others.

Aryl groups are cyclic aromatic hydrocarbons that do not containheteroatoms. Thus aryl groups include, but are not limited to, phenyl,azulenyl, heptalenyl, biphenyl, indacenyl, fluorenyl, phenanthrenyl,triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, biphenylenyl,anthracenyl, and naphthyl groups. In some embodiments, aryl groupscontain 6-14 carbons in the ring portions of the groups. The phrase“aryl groups” includes groups containing fused rings, such as fusedaromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, andthe like), and also includes substituted aryl groups that have othergroups, including but not limited to alkyl, halo, amino, hydroxy, cyano,carboxy, nitro, thio, or alkoxy groups, bonded to one of the ring atoms.Representative substituted aryl groups can be mono-substituted orsubstituted more than once, such as, but not limited to, 2-, 3-, 4-, 5-,or 6-substituted phenyl or naphthyl groups, which can be substitutedwith groups including but not limited to those listed above.

Aralkyl groups are alkyl groups as defined above in which a hydrogen orcarbon bond of an alkyl group is replaced with a bond to an aryl groupas defined above. Representative aralkyl groups include benzyl andphenylethyl groups and fused (cycloalkylaryl)alkyl groups such as4-ethyl-indanyl. The aryl moiety or the alkyl moiety or both areoptionally substituted with other groups, including but not limited toalkyl, halo, amino, hydroxy, cyano, carboxy, nitro, thio, or alkoxygroups. Aralkenyl group are alkenyl groups as defined above in which ahydrogen or carbon bond of an alkyl group is replaced with a bond to anaryl group as defined above.

Heterocyclyl groups include aromatic and non-aromatic ring compoundscontaining 3 or more ring members, of which one or more is a heteroatomsuch as, but not limited to, N, O, S, or P. In some embodiments,heterocyclyl groups include 3 to 20 ring members, whereas other suchgroups have 3 to 15 ring members. At least one ring contains aheteroatom, but every ring in a polycyclic system need not contain aheteroatom. For example, a dioxolanyl ring and a benzdioxolanyl ringsystem (methylenedioxyphenyl ring system) are both heterocyclyl groupswithin the meaning herein. A heterocyclyl group designated as aC₂-heterocyclyl can be a 5-ring with two carbon atoms and threeheteroatoms, a 6-ring with two carbon atoms and four heteroatoms and soforth. Likewise a C₄-heterocyclyl can be a 5-ring with one heteroatom, a6-ring with two heteroatoms, and so forth. The number of carbon atomsplus the number of heteroatoms sums up to equal the total number of ringatoms. The phrase “heterocyclyl group” includes fused ring speciesincluding those having fused aromatic and non-aromatic groups. Thephrase also includes polycyclic ring systems containing a heteroatomsuch as, but not limited to, quinuclidyl and also includes heterocyclylgroups that have substituents, including but not limited to alkyl, halo,amino, hydroxy, cyano, carboxy, nitro, thio, or alkoxy groups, bonded toone of the ring members. A heterocyclyl group as defined herein can be aheteroaryl group or a partially or completely saturated cyclic groupincluding at least one ring heteroatom. Heterocyclyl groups include, butare not limited to, pyrrolidinyl, furanyl, tetrahydrofuranyl,dioxolanyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl,triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl,thiophenyl, benzothiophenyl, benzofuranyl, dihydrobenzofuranyl, indolyl,dihydroindolyl, azaindolyl, indazolyl, benzimidazolyl,azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl,imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl,xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl,tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups.Heterocyclyl groups can be substituted. Representative substitutedheterocyclyl groups can be mono-substituted or substituted more thanonce, including but not limited to, rings containing at least oneheteroatom which are mono, di, tri, tetra, penta, hexa, orhigher-substituted with substituents such as those listed above,including but not limited to alkyl, halo, amino, hydroxy, cyano,carboxy, nitro, thio, and alkoxy groups.

Heteroaryl groups are aromatic ring compounds containing 5 or more ringmembers, of which, one or more is a heteroatom such as, but not limitedto, N, O, and S. A heteroaryl group designated as a C₂-heteroaryl can bea 5-ring with two carbon atoms and three heteroatoms, a 6-ring with twocarbon atoms and four heteroatoms and so forth. Likewise a C₄-heteroarylcan be a 5-ring with one heteroatom, a 6-ring with two heteroatoms, andso forth. The number of carbon atoms plus the number of heteroatoms sumsup to equal the total number of ring atoms. Heteroaryl groups include,but are not limited to, groups such as pyrrolyl, pyrazolyl, triazolyl,tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl,benzothiophenyl, benzofuranyl, indolyl, azaindolyl, indazolyl,benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl,benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl,thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl,isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,quinoxalinyl, and quinazolinyl groups. The terms “heteroaryl” and“heteroaryl groups” include fused ring compounds such as wherein atleast one ring, but not necessarily all rings, are aromatic, includingtetrahydroquinolinyl, tetrahydroisoquinolinyl, indolyl and 2,3-dihydroindolyl. The term also includes heteroaryl groups that have other groupsbonded to one of the ring members, including but not limited to alkyl,halo, amino, hydroxy, cyano, carboxy, nitro, thio, or alkoxy groups.Representative substituted heteroaryl groups can be substituted one ormore times with groups such as those listed above.

Additional examples of aryl and heteroaryl groups include but are notlimited to phenyl, biphenyl, indenyl, naphthyl (1-naphthyl, 2-naphthyl),N-hydroxytetrazolyl, N-hydroxytriazolyl, N-hydroxyimidazolyl,anthracenyl (1-anthracenyl, 2-anthracenyl, 3-anthracenyl), thiophenyl(2-thienyl, 3-thienyl), furyl (2-furyl, 3-furyl), indolyl, oxadiazolyl,isoxazolyl, quinazolinyl, fluorenyl, xanthenyl, isoindanyl, benzhydryl,acridinyl, thiazolyl, pyrrolyl (2-pyrrolyl), pyrazolyl (3-pyrazolyl),imidazolyl (1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl),triazolyl (1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl 1,2,3-triazol-4-yl,1,2,4-triazol-3-yl), oxazolyl (2-oxazolyl, 4-oxazolyl, 5-oxazolyl),thiazolyl (2-thiazolyl, 4-thiazolyl, 5-thiazolyl), pyridyl (2-pyridyl,3-pyridyl, 4-pyridyl), pyrimidinyl (2-pyrimidinyl, 4-pyrimidinyl,5-pyrimidinyl, 6-pyrimidinyl), pyrazinyl, pyridazinyl (3-pyridazinyl,4-pyridazinyl, 5-pyridazinyl), quinolyl (2-quinolyl, 3-quinolyl,4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl), isoquinolyl(1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl,6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl), benzo[b]furanyl(2-benzo[b]furanyl, 3-benzo[b]furanyl, 4-benzo[b]furanyl,5-benzo[b]furanyl, 6-benzo[b]furanyl, 7-benzo[b]furanyl),2,3-dihydro-benzo[b]furanyl (2-(2,3-dihydro-benzo[b]furanyl),3-(2,3-dihydro-benzo[b]furanyl), 4-(2,3-dihydro-benzo[b]furanyl),5-(2,3-dihydro-benzo[b]furanyl), 6-(2,3-dihydro-benzo[b]furanyl),7-(2,3-dihydro-benzo[b]furanyl), benzo[b]thiophenyl(2-benzo[b]thiophenyl, 3-benzo[b]thiophenyl, 4-benzo[b]thiophenyl,5-benzo[b]thiophenyl, 6-benzo[b]thiophenyl, 7-benzo[b]thiophenyl),2,3-dihydro-benzo[b]thiophenyl, (2-(2,3-dihydro-benzo[b]thiophenyl),3-(2,3-dihydro-benzo[b]thiophenyl), 4-(2,3-dihydro-benzo[b]thiophenyl),5-(2,3-dihydro-benzo[b]thiophenyl), 6-(2,3-dihydro-benzo[b]thiophenyl),7-(2,3-dihydro-benzo[b]thiophenyl), indolyl (1-indolyl, 2-indolyl,3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl), indazole(1-indazolyl, 3-indazolyl, 4-indazolyl, 5-indazolyl, 6-indazolyl,7-indazolyl), benzimidazolyl (1-benzimidazolyl, 2-benzimidazolyl,4-benzimidazolyl, 5-benzimidazolyl, 6-benzimidazolyl, 7-benzimidazolyl,8-benzimidazolyl), benzoxazolyl (1-benzoxazolyl, 2-benzoxazolyl),benzothiazolyl (1-benzothiazolyl, 2-benzothiazolyl, 4-benzothiazolyl,5-benzothiazolyl, 6-benzothiazolyl, 7-benzothiazolyl), carbazolyl(1-carbazolyl, 2-carbazolyl, 3-carbazolyl, 4-carbazolyl),5H-dibenz[b,f]azepine (5H-dibenz[b,f]azepin-1-yl,5H-dibenz[b,f]azepine-2-yl, 5H-dibenz[b,f]azepine-3-yl,5H-dibenz[b,f]azepine-4-yl, 5H-dibenz[b,f]azepine-5-yl),10,11-dihydro-5H-dibenz[b,f]azepine(10,11-dihydro-5H-dibenz[b,f]azepine-1-yl,10,11-dihydro-5H-dibenz[b,f]azepine-2-yl,10,11-dihydro-5H-dibenz[b,f]azepine-3-yl,10,11-dihydro-5H-dibenz[b,f]azepine-4-yl,10,11-dihydro-5H-dibenz[b,f]azepine-5-yl), and the like.

Heterocyclylalkyl groups are alkyl groups as defined above in which ahydrogen or carbon bond of an alkyl group is replaced with a bond to aheterocyclyl group as defined above. Representative heterocyclyl alkylgroups include, but are not limited to, furan-2-yl methyl, furan-3-ylmethyl, pyridine-2-yl methyl (α-picolyl), pyridine-3-yl methyl(β-picolyl), pyridine-4-yl methyl (γ-picolyl), tetrahydrofuran-2-ylethyl, and indol-2-yl propyl. Heterocyclylalkyl groups can besubstituted on the heterocyclyl moiety, the alkyl moiety, or both.

Heteroarylalkyl groups are alkyl groups as defined above in which ahydrogen or carbon bond of an alkyl group is replaced with a bond to aheteroaryl group as defined above. Heteroarylalkyl groups can besubstituted on the heteroaryl moiety, the alkyl moiety, or both.

By a “ring system” as the term is used herein is meant a moietycomprising one, two, three or more rings, which can be substituted withnon-ring groups or with other ring systems, or both, which can be fullysaturated, partially unsaturated, fully unsaturated, or aromatic, andwhen the ring system includes more than a single ring, the rings can befused, bridging, or spirocyclic. By “spirocyclic” is meant the class ofstructures wherein two rings are fused at a single tetrahedral carbonatom, as is well known in the art.

A “monocyclic, bicyclic or polycyclic, aromatic or partially aromaticring” as the term is used herein refers to a ring system including anunsaturated ring possessing 4n+2 pi electrons, or a partially reduced(hydrogenated) form thereof. The aromatic or partially aromatic ring caninclude additional fused, bridged, or spiro rings that are notthemselves aromatic or partially aromatic. For example, naphthalene andtetrahydronaphthalene are both a “monocyclic, bicyclic or polycyclic,aromatic or partially aromatic ring” within the meaning herein. Also,for example, a benzo-[2.2.2]-bicyclooctane is also a “monocyclic,bicyclic or polycyclic, aromatic or partially aromatic ring” within themeaning herein, containing a phenyl ring fused to a bridged bicyclicsystem. A fully saturated ring has no double bonds therein, and iscarbocyclic or heterocyclic depending on the presence of heteroatomswithin the meaning herein.

The term “alkoxy” refers to an oxygen atom connected to an alkyl group,including a cycloalkyl group, as are defined above. Examples of linearalkoxy groups include but are not limited to methoxy, ethoxy, n-propoxy,n-butoxy, n-pentyloxy, n-hexyloxy, and the like. Examples of branchedalkoxy include but are not limited to isopropoxy, sec-butoxy,tert-butoxy, isopentyloxy, isohexyloxy, and the like. Examples of cyclicalkoxy include but are not limited to cyclopropyloxy, cyclobutyloxy,cyclopentyloxy, cyclohexyloxy, and the like.

The terms “aryloxy” and “arylalkoxy” refer to, respectively, an arylgroup bonded to an oxygen atom and an aralkyl group bonded to the oxygenatom at the alkyl moiety. Examples include but are not limited tophenoxy, naphthyloxy, and benzyloxy.

An “acyl” group as the term is used herein refers to a group containinga carbonyl moiety wherein the group is bonded via the carbonyl carbonatom. The carbonyl carbon atom is also bonded to another carbon atom,which can be part of an alkyl, aryl, aralkyl cycloalkyl,cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl,heteroarylalkyl group or the like. In the special case wherein thecarbonyl carbon atom is bonded to a hydrogen, the group is a “formyl”group, an acyl group as the term is defined herein. An acyl group caninclude 0 to about 12-20 additional carbon atoms bonded to the carbonylgroup. An acyl group can include double or triple bonds within themeaning herein. An acryloyl group is an example of an acyl group. Anacyl group can also include heteroatoms within the meaning here. Anicotinoyl group (pyridyl-3-carbonyl) group is an example of an acylgroup within the meaning herein. Other examples include acetyl, benzoyl,phenylacetyl, pyridylacetyl, cinnamoyl, and acryloyl groups and thelike. When the group containing the carbon atom that is bonded to thecarbonyl carbon atom contains a halogen, the group is termed a“haloacyl” group. An example is a trifluoroacetyl group.

The term “amine” includes primary, secondary, and tertiary amineshaving, e.g., the formula N(group)₃ wherein each group can independentlybe H or non-H, such as alkyl, aryl, and the like. Amines include but arenot limited to R—NH₂, for example, alkylamines, arylamines,alkylarylamines; R₂NH wherein each R is independently selected, such asdialkylamines, diarylamines, aralkylamines, heterocyclylamines and thelike; and R3N wherein each R is independently selected, such astrialkylamines, dialkylarylamines, alkyldiarylamines, triarylamines, andthe like. The term “amine” also includes ammonium ions as used herein.

An “amino” group is a substituent of the form —NH₂, —NHR, —NR₂, —NR₃ ⁺,wherein each R is independently selected, and protonated forms of each.Accordingly, any compound substituted with an amino group can be viewedas an amine.

An “ammonium” ion includes the unsubstituted ammonium ion NH₄ ⁺, butunless otherwise specified, it also includes any protonated orquaternarized forms of amines. Thus, trimethylammonium hydrochloride andtetramethylammonium chloride are both ammonium ions, and amines, withinthe meaning herein.

The term “amide” (or “amido”) includes C- and N-amide groups, i.e.,—C(O)NR₂, and —NRC(O)R groups, respectively. Amide groups thereforeinclude but are not limited to carbamoyl groups (—C(O)NH₂) and formamidegroups (—NHC(O)H). A “carboxamido” group is a group of the formulaC(O)NR₂, wherein R can be H, alkyl, aryl, etc.

The term “urethane” (or “carbamyl”) includes N- and O-urethane groups,i.e., —NRC(O)OR and —OC(O)NR₂ groups, respectively.

The term “sulfonamide” (or “sulfonamido”) includes S- and N-sulfonamidegroups, i.e., —SO₂NR₂ and —NRSO₂R groups, respectively. Sulfonamidegroups therefore include but are not limited to sulfamoyl groups(—SO₂NH₂).

The term “amidine” or “amidino” includes groups of the formula—C(NR)NR₂. Typically, an amidino group is —C(NH)NH₂.

The term “guanidine” or “guanidino” includes groups of the formula—NRC(NR)NR₂. Typically, a guanidino group is —NHC(NH)NH₂.

“Halo,” “halogen,” and “halide” include fluorine, chlorine, bromine andiodine.

The terms “comprising,” “including,” “having,” “composed of,” areopen-ended terms as used herein, and do not preclude the existence ofadditional elements or components. In a claim element, use of the forms“comprising,” “including,” “having,” or “composed of” means thatwhatever element is comprised, had, included, or composes is notnecessarily the only element encompassed by the subject of the clausethat contains that word.

A “salt” as is well known in the art includes an organic compound suchas a carboxylic acid, a sulfonic acid, or an amine, in ionic form, incombination with a counterion. For example, acids in their anionic formcan form salts with cations such as metal cations, for example sodium,potassium, and the like; with ammonium salts such as NH₄ ⁺ or thecations of various amines, including tetraalkyl ammonium salts such astetramethylammonium, or other cations such as trimethylsulfonium, andthe like. A “pharmaceutically acceptable” or “pharmacologicallyacceptable” salt is a salt formed from an ion that has been approved forhuman consumption and is generally non-toxic, such as a chloride salt ora sodium salt. A “zwitterion” is an internal salt such as can be formedin a molecule that has at least two ionizable groups, one forming ananion and the other a cation, which serve to balance each other. Forexample, amino acids such as glycine can exist in a zwitterionic form. A“zwitterion” is a salt within the meaning herein. The compounds of thepresent invention may take the form of salts. The term “salts” embracesaddition salts of free acids or free bases which are compounds of theinvention. Salts can be “pharmaceutically-acceptable salts.” The term“pharmaceutically-acceptable salt” refers to salts which possesstoxicity profiles within a range that affords utility in pharmaceuticalapplications. Pharmaceutically unacceptable salts may nonethelesspossess properties such as high crystallinity, which have utility in thepractice of the present invention, such as for example utility inprocess of synthesis, purification or formulation of compounds of theinvention.

Suitable pharmaceutically-acceptable acid addition salts may be preparedfrom an inorganic acid or from an organic acid. Examples of inorganicacids include hydrochloric, hydrobromic, hydriodic, nitric, carbonic,sulfuric, and phosphoric acids. Appropriate organic acids may beselected from aliphatic, cycloaliphatic, aromatic, araliphatic,heterocyclic, carboxylic and sulfonic classes of organic acids, examplesof which include formic, acetic, propionic, succinic, glycolic,gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic,fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic,4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic),methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic,trifluoromethanesulfonic, 2-hydroxyethanesulfonic, p-toluenesulfonic,sulfanilic, cyclohexylaminosulfonic, stearic, alginic, β-hydroxybutyric,salicylic, galactaric and galacturonic acid. Examples ofpharmaceutically unacceptable acid addition salts include, for example,perchlorates and tetrafluoroborates.

Suitable pharmaceutically acceptable base addition salts of compounds ofthe invention include, for example, metallic salts including alkalimetal, alkaline earth metal and transition metal salts such as, forexample, calcium, magnesium, potassium, sodium and zinc salts.Pharmaceutically acceptable base addition salts also include organicsalts made from basic amines such as, for example,N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine,ethylenediamine, meglumine (N-methylglucamine) and procaine. Examples ofpharmaceutically unacceptable base addition salts include lithium saltsand cyanate salts. Although pharmaceutically unacceptable salts are notgenerally useful as medicaments, such salts may be useful, for exampleas intermediates in the synthesis of Formula I compounds, for example intheir purification by recrystallization. All of these salts may beprepared by conventional means from the corresponding compound accordingto Formula I by reacting, for example, the appropriate acid or base withthe compound according to Formula I. The term “pharmaceuticallyacceptable salts” refers to nontoxic inorganic or organic acid and/orbase addition salts, see, for example, Lit et al., Salt Selection forBasic Drugs (1986), Int J. Pharm., 33, 201-217, incorporated byreference herein.

A “hydrate” is a compound that exists in a composition with watermolecules. The composition can include water in stoichiometicquantities, such as a monohydrate or a dihydrate, or can include waterin random amounts. As the term is used herein a “hydrate” refers to asolid form, i.e., a compound in water solution, while it may behydrated, is not a hydrate as the term is used herein.

A “solvate” is a similar composition except that a solvent other thatwater replaces the water. For example, methanol or ethanol can form an“alcoholate”, which can again be stoichiometic or non-stoichiometric. Asthe term is used herein a “solvate” refers to a solid form, i.e., acompound in solution in a solvent, while it may be solvated, is not asolvate as the term is used herein.

A “prodrug” as is well known in the art is a substance that can beadministered to a patient where the substance is converted in vivo bythe action of biochemicals within the patients body, such as enzymes, tothe active pharmaceutical ingredient. Examples of prodrugs includeesters of carboxylic acid groups, which can be hydrolyzed by endogenousesterases as are found in the bloodstream of humans and other mammals.

In addition, where features or aspects of the invention are described interms of Markush groups, those skilled in the art will recognize thatthe invention is also thereby described in terms of any individualmember or subgroup of members of the Markush group. For example, if X isdescribed as selected from the group consisting of bromine, chlorine,and iodine, claims for X being bromine and claims for X being bromineand chlorine are fully described. Moreover, where features or aspects ofthe invention are described in terms of Markush groups, those skilled inthe art will recognize that the invention is also thereby described interms of any combination of individual members or subgroups of membersof Markush groups. Thus, for example, if X is described as selected fromthe group consisting of bromine, chlorine, and iodine, and Y isdescribed as selected from the group consisting of methyl, ethyl, andpropyl, claims for X being bromine and Y being methyl are fullydescribed.

In various embodiments, the compound or set of compounds, either per seor as are used in practice of embodiments of the inventive methods, canbe any one of any of the combinations and/or sub-combinations of thevarious embodiments recited.

Provisos may apply to any of the disclosed categories or embodimentswherein any one or more of the other above disclosed embodiments orspecies may be excluded from such categories or embodiments.

More specifically, the inventive compound can be any of the specificexamples shown below as exemplary compounds of the invention.

Various embodiments of the invention provide a compound of formula (I)or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer,hydrate, or solvate thereof:

wherein

a dashed line signifies that a single bond or a double bond can bepresent, provided that there are two double bonds and three single bondsin the ring comprising A¹, A², and A³;

A¹, A², and A³ each independently is C or O or is N when the N is bondedto two adjacent ring atoms by a double bond and a single bond or is NRwherein R is H or (C₁-C₆)alkyl when the N is bonded to two adjacent ringatoms by two single bonds; provided that no more than one of A¹, A², andA³ is C and that at least one of A¹, A², and A³ is N or NR; providedthat only one of A¹, A², and A³ is O;

L¹ and L² are each independently a bond; (CHR′)_(n) wherein R′ is H or(C₁-C₆)alkyl and n is 1, 2, or 3; or a heteroaryl selected from thegroup consisting of thiophenyl, phenyl, furanyl, or benzothiophenyl andwherein such heteroaryl is substituted with 0-3 J;

J independently at each occurrence is F, Cl, Br, I, OR′, OC(O)N(R′)₂,CN, CF₃, OCF₃, CHF₂, NO₂, R′, O, S, C(O), S(O), methylenedioxy,ethylenedioxy, N(R′)₂, N(R′)CH₂CH₂OR′, SR′, SOR′, SO₂R′, SO₂N(R′)₂,SO₃R′, C(O)R′, C(O)C(O)R′, C(O)CH₂C(O)R′, C(S)R′, C(O)OR′, OC(O)R′,OC(O)OR′, C(O)N(R′)₂, OC(O)N(R′)₂, C(S)N(R′)₂, (CH₂)₀₋₂NHC(O)R′,(CH₂)₀₋₂N(R′)₂, (CH₂)₀₋₂N(R′)N(R′)₂, N(R′)N(R′)C(O)R′,N(R′)N(R′)C(O)OR′, N(R′)N(R′)CON(R′)₂, N(R′)SO₂R′, N(R′)SO₂N(R′)₂,N(R′)C(O)OR′, N(R′)C(O)R′, N(R′)N(R′), N(R′)C(S)R′, N(R′)C(O)N(R′)₂,N(R′)C(S)N(R′)₂, N(COR′)COR′, N(OR′)R′, C(═NH)N(R′)₂, C(O)N(OR′)R′, orC(═NOR′)R′, wherein two J groups together can form a ring; wherein R′ isindependently at each occurrence hydrogen or an alkyl, cycloalkyl, aryl,heterocyclyl, or heteroaryl wherein any alkyl, cycloalkyl, aryl,heterocyclyl or heteroaryl is substituted with 0-3 J; or wherein two R′groups together with a nitrogen atom or with two adjacent nitrogen atomsto which they are bonded can together form a (C₃-C₈)heterocyclylsubstituted with 0-3 J; optionally further comprising 1-3 additionalheteroatoms selected from the group consisting of O, N, S, S(O) andS(O)₂;

R⁵ is a mono- or bicyclic cycloalkyl, aryl, heterocyclyl, or heteroaryl;each of which is substituted with 0-5 J, wherein any cycloalkyl, aryl,heterocyclyl, or heteroaryl can be fused, bridged, or in a spiroconfiguration with one or more additional cycloalkyl, aryl,heterocyclyl, heteroaryl rings, any of which can be monocyclic, bicyclicor polycyclic, saturated, partially unsaturated, or aromatic, and any ofwhich is substituted with 0-5 J;

R⁶ is cycloalkyl, aryl, heterocyclyl, or heteroaryl, wherein anycycloalkyl, aryl, heterocyclyl, or heteroaryl is independently mono- orpluri-substituted with J, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,(C₁-C₆)haloalkyl, hydroxyl, halo, (C₁-C₆)haloalkoxy,cycloalkyl(C₁-C₆)alkyl, heterocyclyl(C₁-C₆)alkyl, aryl(C₁-C₆)alkyl,heteroaryl(C₁-C₆)alkyl, OR³ wherein R³ comprises H or (C₁-C₆)alkyl orNR⁴ ₂ wherein each R⁴ independently comprises H or (C₁-C₆)alkyl or wheretwo R⁴ groups together with a nitrogen atom to which they are bondedform a (C₃-C₈)heterocyclyl which optionally further comprises 1-3heteroatoms selected from the group consisting of N, O, S, S(O) andS(O)₂; or R⁴ is optionally substituted cycloalkyl, optionallysubstituted aryl, optionally substituted heterocyclyl, or optionallysubstituted heteroaryl;

wherein any alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, R³,R⁴, cycloalkyl, aryl, heterocyclyl, or heteroaryl can be furthersubstituted with J;

and

provided that (i), (ii), (iii) or (iv) applies:

(i) L¹ is bond or (CHR′)_(n) and R⁵ is a bicyclic ring moiety which isoptionally substituted with 0-5 J where the bicyclic ring moiety is anyone of a-i to a-xxviii wherein a wavy line indicates a point ofattachment:

provided that when R⁵ is either a-xvii or a-xix that L² is bond or(CHR′)_(n);

(ii) L¹ and L² are each independently a bond or (CHR′)_(n); R⁵ is a6-membered heteroaryl ring moiety optionally substituted with 0-3 J¹,wherein J¹ is OR′, CF₃, Cl, Br, F, CN, O(C₁-C₆)alkoxy,O(C₁-C₆)cycloalkoxy, alkyl, or N(R′)₂ and wherein the 6-memberedheteroaryl ring moiety is any one of b-i to b-xiii wherein a wavy lineindicates a point of attachment:

(iii) L¹ is a bond or (CHR′)_(n), and L² is a heteroaryl substitutedwith 0-3 J wherein the heteroaryl is c-i or c-ii wherein a wavy lineindicates a point of attachment:

or

(iv) L¹ is a bond or (CHR′)_(n) and L² is a bond or (CHR′)_(n) or aphenyl substituted with 0-5 J; and R⁵ and R⁶ are independently selectedfrom phenyl or heteroaryl each optionally substituted with 0-5occurrences of J; provided that if L² is a bond and R⁵ and R⁶ are bothphenyl, then R⁵ is substituted with at least one of 4-CN, 3-alkyl-NHR′,3-alkyl-OR′, 4-alkyl-OR′, or 2,3-dialkyl and R⁶ is substituted with atleast 4-OR′; provided, that when (ii), (iii), or (iv) applies, that thecompound of formula (I) is not one of the following:

In various embodiments of a compound of the invention, L² is bond.

In various embodiments of a compound of the invention, A¹ and A³ are Nand A² is O.

In various embodiments of a compound of the invention, A² and A³ are Nand A¹ is O, or A¹ and A² are N and A³ is O.

In various embodiments of a compound of the invention, A¹ and A² are Nand A³ is NR.

In various embodiments of a compound of the invention, A¹ is C, A² is Nand A³ is O.

In various embodiments of a compound of the invention, A¹ is O, A² is Nand A³ is C.

In various embodiments of a compound of the invention, L¹ and L² areeach independently a bond or (CHR′)_(n), and R⁵ or R⁶, or both,comprises a heteroaryl ring. For example, at least one heteroaryl ringof R⁵ or R⁶ can be a pyridinyl or a pyridinyl N-oxide, pyrazinyl,pyrrolyl, imidazolyl, benzimidazolyl, thiophenyl, benzothiophenyl,furyl, benzofuryl, indolyl, indolinyl, piperidinyl, quinolyl, orisoquinolyl; wherein any heteroaryl is substituted with 0-5 J. Morespecifically, any heteroaryl can be substituted with 0-5 R′, F, Cl, Br,I, OR′, CF₃, OCF₃, CHF₂, or SO₂N(R′)₂.

In various embodiments of a compound of the invention, L¹ and L² areeach independently a bond or (CHR′)_(n), and R⁵ or R⁶, or both,comprises a bicyclic carbocyclic ring, wherein the bicyclic carbocyclicring is substituted with 0-5 J. More specifically, any bicycliccarbocyclic ring can be substituted with 0-5 R′, F, Cl, Br, I, OR′, CF₃,OCF₃, CHF₂, or SO₂N(R′)₂.

For example, L¹ can be bond and R⁵ be a bicyclic ring moiety which issubstituted with 0-5 J where the bicyclic ring moiety is any one of a-ito a-xxviii, wherein a wavy line indicates a point of attachment:

wherein any of the bicyclic ring moieties is substituted with 0-5 J.

For example, L¹ and L² cab each be a bond; and R⁵ can be a 6-memberedheteroaryl ring moiety substituted with 0-3 occurrences of J¹; whereinJ¹ is selected from the group consisting of OR′, CF₃, Cl, Br, F, CN,O(C₁-C₆)alkoxy, O(C₁-C₆)cycloalkoxy, alkyl, N(R′)₂; and wherein theoptionally substituted 6-membered heteroaryl ring moiety of R⁵ is anyone of b-i to b-xiii:

wherein each of the 6-membered heteroaryl ring moieties is substitutedwith 0-3 J¹.

In various embodiments of a compound of the invention, L¹ can be a bond,and L² can be c-i or c-ii wherein a wavy line indicates a point ofattachment:

wherein c-i and c-ii are further substituted with 0-2 J.

In various embodiments of a compound of the invention, L¹ can be a bondand L² can be a bond or a phenyl substituted with 0-5 J; and R⁵ and R⁶can independently be selected from phenyl or heteroaryl each substitutedwith 0-5 J; provided that if L² is a bond and R⁵ and R⁶ are both phenyl,then R⁵ is substituted with at least one of 4-CN, 3-alkyl-N(R′)₂,3-alkyl-OR′, 4-alkyl-OR′, or 2,3-dialkyl, and R⁶ is substituted with atleast 4-OR′.

For example, the optionally substituted bicyclic ring moiety can be anyone of a-i to a-viii.

wherein any of the bicyclic ring moieties is substituted with 0-5 J.

For example, a compound of the invention can have the formula I-Bfurther substituted with 0-5 J:

For example, a compound of the invention can have the formula I-Cfurther substituted with 0-5 J:

For example, a compound of the invention can have the formula I-D andfurther be substituted with 0-5 J, and wherein R⁷ and R⁸ eachindependently are H, OR′, OC(O)N(R′)₂, N(R′)N(R′)₂, N(R′)CH₂CH₂OR′, CN,CHF₂, CF₃, OCF₃, NO₂, R′, ═O, ═S, C(O), S(O), N(R′)₂, SR′, SOR′, SO₂R′,SO₂N(R′)₂, SO₃R′, or C(O)R′, or R⁷ and R⁸ together are ═O, ═NR′, or═N(R′)CH₂CH₂OR′.

For example, a compound of the invention can have a formula I-F

wherein R⁷ and R⁸ are each independently selected from H, OR″, N(R″)₂,and SR′, wherein R″ is hydrogen or an alkyl, cycloalkyl, aryl,heterocyclyl, or heteroaryl, wherein any such alkyl, cycloalkyl, aryl,heterocyclyl or heteroaryl is substituted with 0-3 J; X is F, Cl, Br, I,CHF₂, CN, CF₃, NO₂, or OR′; Y is hydrogen or an alkyl, cycloalkyl, aryl,heterocyclyl, or heteroaryl, wherein any such alkyl, cycloalkyl, aryl,heterocyclyl or heteroaryl is substituted with 0-3 J.

In various embodiments of a compound of the invention can be any of:

or any pharmaceutically acceptable salt, tautomer, stereoisomer,solvate, hydrate, or prodrug thereof.

In various embodiments of a compound of the invention, the bicyclic ringmoiety can be any one of a-ix to a-xv:

wherein any of the bicyclic ring moieties can be substituted with 0-5 J.

More specifically, in various embodiments of a compound of theinvention, the compound can be any of:

or any pharmaceutically acceptable salt, tautomer, stereoisomer,solvate, hydrate, or prodrug thereof.

In various embodiments of a compound of the invention, the optionallysubstituted bicyclic ring moiety can be any one of a-xvi to a-xxv:

wherein any of the bicyclic ring moieties is substituted with 0-5 J.

In various embodiments of a compound of the invention, the compound canbe any of:

or any pharmaceutically acceptable salt, tautomer, stereoisomer,solvate, hydrate, or prodrug thereof.

In various embodiments of a compound of the invention, the optionallysubstituted 6-membered heteroaryl ring moiety of R⁵ can be any one ofb-i to b-v.

wherein any of the 6-membered heteroaryl ring moieties is substitutedwith 0-3 J¹.

In various embodiments of a compound of the invention, the compound canbe any of:

or any pharmaceutically acceptable salt, tautomer, stereoisomer,solvate, hydrate, or prodrug thereof.More specifically, in various embodiments of a compound of theinvention, the compound can be any of:

or any pharmaceutically acceptable salt, tautomer, stereoisomer,solvate, hydrate, or prodrug thereof.

In various embodiments of a compound of the invention, the compound canbe any of:

or any pharmaceutically acceptable salt, tautomer, stereoisomer,solvate, hydrate, or prodrug thereof.

More specifically, the compound can be any of the following:

or any pharmaceutically acceptable salt, tautomer, stereoisomer,solvate, hydrate, or prodrug thereof.

More specifically, the compound can be any of:

or any pharmaceutically acceptable salt, tautomer, stereoisomer,solvate, hydrate, or prodrug thereof.

In various embodiments the invention provides a pharmaceuticalcomposition comprising a compound of the invention and a suitableexcipient.

In various embodiments the invention provides a pharmaceuticalcombination comprising the compound of the invention and a secondmedicament. For example, the second medicament can be medicallyindicated for the treatment of multiple sclerosis, transplant rejection,or adult respiratory distress syndrome.

Various embodiments of the invention provide a method of activation,agonism, inhibition, or antagonism of a sphingosine-1-phosphate receptorsubtype 1 comprising contacting the receptor subtype 1 with an effectiveamount of a compound of formula (II) or a pharmaceutically acceptablesalt, prodrug, tautomer, stereoisomer, hydrate, or solvate thereof:

wherein

a dashed line signifies that a single bond or a double bond can bepresent, provided that there are two double bonds and three single bondsin the ring comprising A¹, A², and A³;

A¹, A², and A³ each independently is C or O or is N when the N is bondedto two adjacent ring atoms by a double bond and a single bond or is NRwherein R is H or (C₁-C₆)alkyl when the N is bonded to two adjacent ringatoms by two single bonds; provided that no more than one of A¹, A², andA³ is C and that at least one of A¹, A², and A³ is N or NR; providedthat only one of A¹, A², and A³ is O;

L¹ and L² are each independently a bond; (CHR′)_(n) wherein R′ is H or(C₁-C₆)alkyl and n is 1, 2, or 3; or a heteroaryl selected from thegroup consisting of thiophenyl, phenyl, furanyl, or benzothiophenyl andwherein such heteroaryl is substituted with 0-3 J;

J independently at each occurrence is F, Cl, Br, I, OR′, OC(O)N(R′)₂,CN, CF₃, OCF₃, CHF₂, NO₂, R′, O, S, C(O), S(O), methylenedioxy,ethylenedioxy, N(R′)₂, N(R′)CH₂CH₂OR′, SR′, SOR′, SO₂R′, SO₂N(R′)₂,SO₃R′, C(O)R′, C(O)C(O)R′, C(O)CH₂C(O)R′, C(S)R′, C(O)OR′, OC(O)R′,OC(O)OR′, C(O)N(R′)₂, OC(O)N(R′)₂, C(S)N(R′)₂, (CH₂)₀₋₂NHC(O)R′,(CH₂)₀₋₂N(R′)₂, (CH₂)₀₋₂N(R′)N(R′)₂, N(R′)N(R′)C(O)R′,N(R′)N(R′)C(O)OR′, N(R′)N(R′)CON(R′)₂, N(R′)SO₂R′, N(R′)SO₂N(R′)₂,N(R′)C(O)OR′, N(R′)C(O)R′, N(R′)N(R′), N(R′)C(S)R′, N(R′)C(O)N(R′)₂,N(R′)C(S)N(R′)₂, N(COR′)COR′, N(OR′)R′, C(═NH)N(R′)₂, C(O)N(OR′)R′, orC(═NOR′)R′, wherein two J groups together can form a ring; wherein R′ isindependently at each occurrence hydrogen or an alkyl, cycloalkyl, aryl,heterocyclyl, or heteroaryl wherein any alkyl, cycloalkyl, aryl,heterocyclyl or heteroaryl is substituted with 0-3 J; or wherein two R′groups together with a nitrogen atom or with two adjacent nitrogen atomsto which they are bonded can together form a (C₃-C₈)heterocyclylsubstituted with 0-3 J; optionally further comprising 1-3 additionalheteroatoms selected from the group consisting of O, N, S, S(O) andS(O)₂;

R⁵ is a mono- or bicyclic cycloalkyl, aryl, heterocyclyl, or heteroaryl;each of which is substituted with 0-5 J, wherein any cycloalkyl, aryl,heterocyclyl, or heteroaryl can be fused, bridged, or in a spiroconfiguration with one or more additional cycloalkyl, aryl,heterocyclyl, heteroaryl rings, any of which can be monocyclic, bicyclicor polycyclic, saturated, partially unsaturated, or aromatic, and any ofwhich is substituted with 0-5 J;

R⁶ is cycloalkyl, aryl, heterocyclyl, or heteroaryl, wherein anycycloalkyl, aryl, heterocyclyl, or heteroaryl is independently mono- orpluri-substituted with J, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,(C₁-C₆)haloalkyl, hydroxyl, halo, (C₁-C₆)haloalkoxy,cycloalkyl(C₁-C₆)alkyl, heterocyclyl(C₁-C₆)alkyl, aryl(C₁-C₆)alkyl,heteroaryl(C₁-C₆)alkyl, OR³ wherein R³ comprises H or (C₁-C₆)alkyl orNR⁴ ₂ wherein each R⁴ independently comprises H or (C₁-C₆)alkyl or wheretwo R⁴ groups together with a nitrogen atom to which they are bondedform a (C₃-C₈)heterocyclyl which optionally further comprises 1-3heteroatoms selected from the group consisting of N, O, S, S(O) andS(O)₂; or R⁴ is optionally substituted cycloalkyl, optionallysubstituted aryl, optionally substituted heterocyclyl, or optionallysubstituted heteroaryl;

wherein any alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, R³,R⁴, cycloalkyl, aryl, heterocyclyl, or heteroaryl can be furthersubstituted with J;

and

provided that (i), (ii), (iii) or (iv) applies:

(i) L¹ is bond or (CHR′)_(n) and R⁵ is a bicyclic ring moiety which isoptionally substituted with 0-5 J where the bicyclic ring moiety is anyone of a-i to a-xxviii wherein a wavy line indicates a point ofattachment:

provided that when R⁵ is either a-xvii or a-xix that L² is bond or(CHR′)_(n);

(ii) L¹ and L² are each independently a bond or (CHR′)_(n); R⁵ is a6-membered heteroaryl ring moiety optionally substituted with 0-3 J¹,wherein J¹ is OR′, CF₃, Cl, Br, F, CN, O(C₁-C₆)alkoxy,O(C₁-C₆)cycloalkoxy, alkyl, or N(R′)₂ and wherein the 6-memberedheteroaryl ring moiety is any one of b-i to b-xiii wherein a wavy lineindicates a point of attachment:

(iii) L¹ is a bond or (CHR′)_(n), and L² is a heteroaryl substitutedwith 0-3 J wherein the heteroaryl is c-i or c-ii wherein a wavy lineindicates a point of attachment:

or

(iv) L¹ is a bond or (CHR′)_(n) and L² is a bond or (CHR′)_(n) or aphenyl substituted with 0-5 J; and R⁵ and R⁶ are independently selectedfrom phenyl or heteroaryl each optionally substituted with 0-5occurrences of J; provided that if L² is a bond and R⁵ and R⁶ are bothphenyl, then R⁵ is substituted with at least one of 4-CN, 3-alkyl-NHR′,3-alkyl-OR′, 4-alkyl-OR′, or 2,3-dialkyl and R⁶ is substituted with atleast 4-OR′;

provided, that when (ii), (iii), or (iv) applies, that the compound offormula (I) is not one of the following:

In various embodiments, a method of the invention uses a compoundwherein L² is bond.

In various embodiments, a method of the invention uses a compoundwherein A¹ and A³ are N and A² is O, or wherein A² and A³ are N and A¹is O, or wherein A¹ and A² are N and A³ is O, or wherein A¹ and A² are Nand A³ is NR.

In various embodiments, a method of the invention uses a compoundwherein A¹ is C, A² is N and A³ is O, or wherein A¹ is O, A² is N and A³is C, or wherein L¹ and L² are each independently a bond or (CHR′)_(n),and R⁵ or R⁶, or both, comprises a heteroaryl ring. For example, atleast one heteroaryl ring of R⁵ or R⁶ can be pyridinyl or a pyridinylN-oxide, pyrazinyl, pyrrolyl, imidazolyl, benzimidazolyl, thiophenyl,benzothiophenyl, furyl, benzofuryl, indolyl, indolinyl, piperidinyl,quinolyl, or isoquinolyl; wherein any heteroaryl can be substituted with0-5 J. More specifically, any heteroaryl can be substituted with 0-5 R′,F, Cl, Br, I, OR′, CF₃, OCF₃, CHF₂, or SO₂N(R′)₂.

In various embodiments, a method of the invention uses a compoundwherein L¹ and L² are each independently a bond or (CHR′)_(n), and R⁵ orR⁶, or both, comprises a bicyclic carbocyclic ring, wherein the bicycliccarbocyclic ring is substituted with 0-5 J. For example, any bicycliccarbocyclic ring can be substituted with 0-5 R′, F, Cl, Br, I, OR′, CF₃,OCF₃, CHF₂, or SO₂N(R′)₂.

In various embodiments, a method of the invention uses a compoundwherein L¹ is bond and R⁵ is a bicyclic ring moiety which is substitutedwith 0-5 J where the bicyclic ring moiety is any one of a-i to a-xxviii,wherein a wavy line indicates a point of attachment:

wherein any of the bicyclic ring moieties is substituted with 0-5 J.

In various embodiments, a method of the invention uses a compoundwherein L¹ and L² are each a bond; R⁵ is a 6-membered heteroaryl ringmoiety substituted with 0-3 occurrences of J¹; wherein J¹ is selectedfrom the group consisting of OR′, CF₃, Cl, Br, F, CN, O(C₁-C₆)alkoxy,O(C₁-C₆)cycloalkoxy, alkyl, N(R′)₂; and wherein the optionallysubstituted 6-membered heteroaryl ring moiety of R⁵ is any one of b-i tob-xiii:

wherein each of the 6-membered heteroaryl ring moieties is substitutedwith 0-3 J¹, or wherein L¹ is a bond, and L² is c-i or c-ii, wherein awavy line indicates a point of attachment:

wherein c-i and c-ii are further substituted with 0-2 J.

In various embodiments, a method of the invention uses a compoundwherein L¹ is a bond and L² is a bond or is phenyl substituted with 0-5J; and R⁵ and R⁶ are independently selected from phenyl or heteroaryleach substituted with 0-5 J; provided that if L² is a bond and R⁵ and R⁶are both phenyl, then R⁵ is substituted with at least one of 4-CN,3-alkyl-N(R′)₂, 3-alkyl-OR′, 4-alkyl-OR′, or 2,3-dialkyl, and R⁶ issubstituted with at least 4-OR′.

In various embodiments, the optionally substituted bicyclic ring moietycan be any one of a-i to a-viii.

wherein any of the bicyclic ring moieties is substituted with 0-5 J.

In various embodiments, a method of the invention uses a compound havingthe formula I-B further substituted with 0-5 J:

I-B, or having the formula I-C further substituted with 0-5 J:

I-C, or having the formula I-D and further substituted with 0-5 J, andwherein R⁷ and R⁸ each independently are H, OR′, OC(O)N(R′)₂,N(R′)N(R′)₂, N(R′)CH₂CH₂OR′, CN, CHF₂, CF₃, OCF₃, NO₂, R′, ═O, ═S, C(O),S(O), N(R′)₂, SR′, SOR′, SO₂R′, SO₂N(R′)₂, SO₃R′, or C(O)R′, or R⁷ andR⁸ together are ═O, ═NR′, or ═N(R′)CH₂CH₂OR′.

1-D, or wherein the compound has a formula I-F

wherein R⁷ and R⁸ are each independently selected from H, OR″, N(R″)₂,and SR′, wherein R″ is hydrogen or an alkyl, cycloalkyl, aryl,heterocyclyl, or heteroaryl, wherein any such alkyl, cycloalkyl, aryl,heterocyclyl or heteroaryl is substituted with 0-3 J; X is F, Cl, Br, I,CHF₂, CN, CF₃, NO₂, or OR′; Y is hydrogen or an alkyl, cycloalkyl, aryl,heterocyclyl, or heteroaryl, wherein any such alkyl, cycloalkyl, aryl,heterocyclyl or heteroaryl is substituted with 0-3 J.

In various embodiments, a method of the invention uses a compoundwherein the compound is any of the

following:

In various embodiments, a method of the invention uses a compoundwherein the compound activates or agonizes the sphingosine-1-phosphatereceptor subtype 1 to a greater extent than the compound activates oragonizes another subtype of sphingosine-1-phosphate receptor. Forexample, the other subtype of sphingosine-1-phosphate receptor can besubtype 3. In various embodiments, the sphingosine-1-phosphate receptorsubtype 1 can be disposed within a living mammal.

In various embodiments, the invention provides a method of treatment ofa malcondition in a patient for which activation, agonism, inhibition,or antagonism of an S1P1 receptor is medically indicated, comprisingcontacting the S1P1 receptor according to a method of the invention byadministering the compound to the patient at a frequency and for aduration of time sufficient to provide a beneficial effect to thepatient. For example, selective activation or agonism of an S1P subtype1 receptor with respect to other subtypes of S1P receptor is medicallyindicated. More specifically, the malcondition can comprise multiplesclerosis, transplant rejection, or adult respiratory distress syndrome.The inventive method can further comprise administering an effectiveamount of a second medicament to the patient, such as wherein the secondmedicament is adapted for treatment of multiple sclerosis, transplantrejection, or adult respiratory distress syndrome.

Compositions and Combination Treatments

The S1P1 compounds, their pharmaceutically acceptable salts orhydrolyzable esters of the present invention may be combined with apharmaceutically acceptable carrier to provide pharmaceuticalcompositions useful for treating the biological conditions or disordersnoted herein in mammalian species, and more preferably, in humans. Theparticular carrier employed in these pharmaceutical compositions may arydepending upon the type of administration desired (e.g. intravenous,oral, topical, suppository, or parenteral).

In preparing the compositions in oral liquid dosage forms (e.g.suspensions, elixirs and solutions), typical pharmaceutical media, suchas water, glycols, oils, alcohols, flavoring agents, preservatives,coloring agents and the like can be employed. Similarly, when preparingoral solid dosage forms (e.g. powders, tablets and capsules), carrierssuch as starches, sugars, diluents, granulating agents, lubricants,binders, disintegrating agents and the like can be employed.

Another aspect of an embodiment of the invention provides compositionsof the compounds of the invention, alone or in combination with anotherS1P1 inhibitor or another type of therapeutic agent, or both. As setforth herein, compounds of the invention include stereoisomers,tautomers, solvates, hydrates, salts including pharmaceuticallyacceptable salts, and mixtures thereof. Compositions containing acompound of the invention can be prepared by conventional techniques,e.g. as described in Remington: The Science and Practice of Pharmacy,19th Ed., 1995, incorporated by reference herein. The compositions canappear in conventional forms, for example capsules, tablets, aerosols,solutions, suspensions or topical applications.

Typical compositions include a compound of the invention and apharmaceutically acceptable excipient which can be a carrier or adiluent. For example, the active compound will usually be mixed with acarrier, or diluted by a carrier, or enclosed within a carrier which canbe in the form of an ampoule, capsule, sachet, paper, or othercontainer. When the active compound is mixed with a carrier, or when thecarrier serves as a diluent, it can be solid, semi-solid, or liquidmaterial that acts as a vehicle, excipient, or medium for the activecompound. The active compound can be adsorbed on a granular solidcarrier, for example contained in a sachet. Some examples of suitablecarriers are water, salt solutions, alcohols, polyethylene glycols,polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin,lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar,cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin,acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid,fatty acids, fatty acid amines, fatty acid monoglycerides anddiglycerides, pentaerythritol fatty acid esters, polyoxyethylene,hydroxymethylcellulose and polyvinylpyrrolidone. Similarly, the carrieror diluent can include any sustained release material known in the art,such as glyceryl monostearate or glyceryl distearate, alone or mixedwith a wax.

The formulations can be mixed with auxiliary agents which do notdeleteriously react with the active compounds. Such additives caninclude wetting agents, emulsifying and suspending agents, salt forinfluencing osmotic pressure, buffers and/or coloring substancespreserving agents, sweetening agents or flavoring agents. Thecompositions can also be sterilized if desired.

The route of administration can be any route which effectivelytransports the active compound of the invention which inhibits theenzymatic activity of the focal adhesion kinase to the appropriate ordesired site of action, such as oral, nasal, pulmonary, buccal,subdermal, intradermal, transdermal or parenteral, e.g., rectal, depot,subcutaneous, intravenous, intraurethral, intramuscular, intranasal,ophthalmic solution or an ointment, the oral route being preferred.

For parenteral administration, the carrier will typically comprisesterile water, although other ingredients that aid solubility or serveas preservatives can also be included. Furthermore, injectablesuspensions can also be prepared, in which case appropriate liquidcarriers, suspending agents and the like can be employed.

For topical administration, the compounds of the present invention canbe formulated using bland, moisturizing bases such as ointments orcreams.

If a solid carrier is used for oral administration, the preparation canbe tabletted, placed in a hard gelatin capsule in powder or pellet formor it can be in the form of a troche or lozenge. If a liquid carrier isused, the preparation can be in the form of a syrup, emulsion, softgelatin capsule or sterile injectable liquid such as an aqueous ornon-aqueous liquid suspension or solution.

Injectable dosage forms generally include aqueous suspensions or oilsuspensions which can be prepared using a suitable dispersant or wettingagent and a suspending agent Injectable forms can be in solution phaseor in the form of a suspension, which is prepared with a solvent ordiluent. Acceptable solvents or vehicles include sterilized water,Ringer's solution, or an isotonic aqueous saline solution.Alternatively, sterile oils can be employed as solvents or suspendingagents. Preferably, the oil or fatty acid is non-volatile, includingnatural or synthetic oils, fatty acids, mono-, di- or tri-glycerides.

For injection, the formulation can also be a powder suitable forreconstitution with an appropriate solution as described above. Examplesof these include, but are not limited to, freeze dried, rotary dried orspray dried powders, amorphous powders, granules, precipitates, orparticulates. For injection, the formulations can optionally containstabilizers, pH modifiers, surfactants, bioavailability modifiers andcombinations of these. The compounds can be formulated for parenteraladministration by injection such as by bolus injection or continuousinfusion. A unit dosage form for injection can be in ampoules or inmulti-dose containers.

The formulations of the invention can be designed to provide quick,sustained, or delayed release of the active ingredient afteradministration to the patient by employing procedures well known in theart. Thus, the formulations can also be formulated for controlledrelease or for slow release.

Compositions contemplated by the present invention can include, forexample, micelles or liposomes, or some other encapsulated form, or canbe administered in an extended release form to provide a prolongedstorage and/or delivery effect. Therefore, the formulations can becompressed into pellets or cylinders and implanted intramuscularly orsubcutaneously as depot injections. Such implants can employ known inertmaterials such as silicones and biodegradable polymers, e.g.,polylactide-polyglycolide. Examples of other biodegradable polymersinclude poly(orthoesters) and poly(anhydrides).

For nasal administration, the preparation can contain a compound of theinvention which inhibits the enzymatic activity of the focal adhesionkinase, dissolved or suspended in a liquid carrier, preferably anaqueous carrier, for aerosol application. The carrier can containadditives such as solubilizing agents, e.g., propylene glycol,surfactants, absorption enhancers such as lecithin (phosphatidylcholine)or cyclodextrin, or preservatives such as parabens.

For parenteral application, particularly suitable are injectablesolutions or suspensions, preferably aqueous solutions with the activecompound dissolved in polyhydroxylated castor oil.

Tablets, dragees, or capsules having talc and/or a carbohydrate carrieror binder or the like are particularly suitable for oral application.Preferable carriers for tablets, dragees, or capsules include lactose,corn starch, and/or potato starch. A syrup or elixir can be used incases where a sweetened vehicle can be employed.

A typical tablet that can be prepared by conventional tablettingtechniques can contain:

Core: Active compound (as free compound or salt thereof) 250 mg Colloidal silicon dioxide (Aerosil) ® 1.5 mg Cellulose, microcryst.(Avicel) ®  70 mg Modified cellulose gum (Ac-Di-Sol) ® 7.5 mg Magnesiumstearate Ad. Coating: HPMC approx.  9 mg *Mywacett 9-40 T approx. 0.9 mg*Acylated monoglyceride used as plasticizer for film coating.

A typical capsule for oral administration contains compounds of theinvention (250 mg), lactose (75 mg) and magnesium stearate (15 mg). Themixture is passed through a 60 mesh sieve and packed into a No. 1gelatin capsule. A typical injectable preparation is produced byaseptically placing 250 mg of compounds of the invention into a vial,aseptically freeze-drying and sealing. For use, the contents of the vialare mixed with 2 mL of sterile physiological saline, to produce aninjectable preparation.

The compounds of the invention can be administered to a human in need ofsuch treatment, prevention, elimination, alleviation or amelioration ofa malcondition that is mediated through the action of S1P1, for example,multiple sclerosis, transplant rejection, and adult respiratory distresssyndrome.

The pharmaceutical compositions and compounds of the present inventioncan generally be administered in the form of a dosage unit (e.g. tablet,capsule, etc.) in an amount from about 1 μ/kg of body weight to about 1g/kg of body weight, preferably from about 5 μ/kg of body weight toabout 500 mg/kg of body weight, more preferably from about 10 μ/kg ofbody weight to about 250 mg/kg of body weight, most preferably fromabout 20 μ/kg of body weight to about 100 mg/kg of body weight. Thoseskilled in the art will recognize that the particular quantity ofpharmaceutical composition and/or compounds of the present inventionadministered to an individual will depend upon a number of factorsincluding, without limitation, the biological effect desired, thecondition of the individual and the individual's tolerance for thecompound.

The compounds of the invention are effective over a wide dosage range.For example, in the treatment of adult humans, dosages from about 0.05to about 5000 mg, preferably from about 1 to about 2000 mg, and morepreferably between about 2 and about 2000 mg per day can be used. Atypical dosage is about 10 mg to about 1000 mg per day. In choosing aregimen for patients it can frequently be necessary to begin with ahigher dosage and when the condition is under control to reduce thedosage. The exact dosage will depend upon the activity of the compound,mode of administration, on the therapy desired, form in whichadministered, the subject to be treated and the body weight of thesubject to be treated, and the preference and experience of thephysician or veterinarian in charge. S1P1 agonist bioactivity of thecompounds of the invention can be determined by use of an in vitro assaysystem which measures the activation of S1P1, which can be expressed asEC₅₀ values, as are well known in the art inhibitors of the inventioncan be determined by the method described in the Examples.

Generally, the compounds of the invention are dispensed in unit dosageform including from about 0.05 mg to about 1000 mg of active ingredienttogether with a pharmaceutically acceptable carrier per unit dosage.

Usually, dosage forms suitable for oral, nasal, pulmonal or transdermaladministration include from about 125 μg to about 1250 mg, preferablyfrom about 250 μg to about 500 mg, and more preferably from about 2.5 mgto about 250 mg, of the compounds admixed with a pharmaceuticallyacceptable carrier or diluent.

Dosage forms can be administered daily, or more than once a day, such astwice or thrice daily. Alternatively dosage forms can be administeredless frequently than daily, such as every other day, or weekly, if foundto be advisable by a prescribing physician.

An embodiment of the invention also encompasses prodrugs of a compoundof the invention which on administration undergo chemical conversion bymetabolic or other physiological processes before becoming activepharmacological substances. Conversion by metabolic or otherphysiological processes includes without limitation enzymatic (e.g,specific enzymatically catalyzed) and non-enzymatic (e.g., general orspecific acid or base induced) chemical transformation of the prodruginto the active pharmacological substance. In general, such prodrugswill be functional derivatives of a compound of the invention which arereadily convertible in vivo into a compound of the invention.Conventional procedures for the selection and preparation of suitableprodrug derivatives are described, for example, in Design of Prodrugs,ed. H. Bundgaard, Elsevier, 1985.

In another embodiment, there are provided methods of making acomposition of a compound described herein including formulating acompound of the invention with a pharmaceutically acceptable carrier ordiluent. In some embodiments, the pharmaceutically acceptable carrier ordiluent is suitable for oral administration. In some such embodiments,the methods can further include the step of formulating the compositioninto a tablet or capsule. In other embodiments, the pharmaceuticallyacceptable carrier or diluent is suitable for parenteral administration.In some such embodiments, the methods further include the step oflyophilizing the composition to form a lyophilized preparation.

The compounds of the invention can be used therapeutically incombination with i) one or more other S1P1 inhibitors and/or ii) one ormore other types of protein kinase inhibitors and/or one or more othertypes of therapeutic agents which can be administered orally in the samedosage form, in a separate oral dosage form (e.g., sequentially ornon-sequentially) or by injection together or separately (e.g.,sequentially or non-sequentially).

Accordingly, in another embodiment the invention provides combinations,comprising:

a) a compound of the invention as described herein; and

b) one or more compounds comprising:

-   -   i) other compounds of the present invention,    -   ii) other medicaments adapted for treatment of a malcondition        for which activation of S1P1 is medically indicated, for example        multiple sclerosis, transplant rejection, or adult respiratory        distress syndrome.

Combinations of the invention include mixtures of compounds from (a) and(b) in a single formulation and compounds from (a) and (b) as separateformulations. Some combinations of the invention can be packaged asseparate formulations in a kit. In some embodiments, two or morecompounds from (b) are formulated together while a compound of theinvention is formulated separately.

The dosages and formulations for the other agents to be employed, whereapplicable, will be as set out in the latest edition of the Physicians'Desk Reference, incorporated herein by reference.

Methods of Treatment

In various embodiments, the present invention provides a method foractivating or agonizing (i.e., to have an agonic effect, to act as anagonist) a sphingosine-1-phosphate receptor subtype, such as S1P1, witha compound of the invention. The method involves contacting the receptorwith a suitable concentration of an inventive compound to bring aboutactivation of the receptor. The contacting can take place in vitro, forexample in carrying out an assay to determine the S1P receptoractivation activity of an inventive compound undergoing experimentationrelated to a submission for regulatory approval.

The method for activating an S1P receptor, such as S1P1, can also becarried out in vivo, that is, within the living body of a mammal, suchas a human patient or a test animal. The inventive compound can besupplied to the living organism via one of the routes as describedabove, e.g., orally, or can be provided locally within the body tissues,for example by injection of a tumor within the organism. In the presenceof the inventive compound, activation of the receptor takes place, andthe effect thereof can be studied.

An embodiment of the present invention provides a method of treatment ofa malcondition in a patient for which activation of an S1P receptor,such as S1P1, is medically indicated, wherein the patient isadministered the inventive compound in a dosage, at a frequency, and fora duration to produce a beneficial effect on the patient. The inventivecompound can be administered by any suitable means, examples of whichare described above.

Experimental Procedures for Studying Agonist-Induced Internalization,Receptor Phosphorylation and Receptor Polyubiquitination in StablyExpressed S1P₁-GFP Cells Materials.

S1P was obtained from Biomol. The S1P receptor agonist, AFD-R, was agift from Dr. Brickman (Novartis Pharma). Anti-GFP antibodies (ab-1218and ab-6556) were from Abcam, anti-ubiquitin P4D1 antibody from SantaCruz, 4-12% Tris-Glycine Novex SDS-PAGE gels from Invitrogen, P³²orthophosphate from Perkin-Elmer. Fetal bovine serum (FBS) andcharcoal-stripped-FBS were from Hyclone, and other culture reagents werefrom the TSRI Supply Center (supplied by Invitrogen and Gibco BRL).

Cell Culture.

HEK-293 cells stably expressing the GFP-tagged human S1P₁ receptor(S1P₁-GFP) and 293-vector-GFP cells were a gift from Dr Timothy Hla(Connecticut Health Science Center). Cells were maintained inhigh-glucose modified Eagle's medium containing GlutaMAX, andsupplemented with 10% FBS, 1% penicillin/streptomycin solution andselected with 500 ug/ml G418 (Gibco BRL).

Microscopy Imaging Studies for Ligand-Mediated S1P₁-GFP Internalization.

Single S1P₁-GFP cells grown in gelatin-coated coverslips were used tostudy ligand induced S1P₁-GFP internalization. Cells were incubatedovernight in charcoal-stripped FBS (cs-FBS) medium before the start ofthe experiment, and all incubations thereafter were done in cs-FBSmedium-containing 15 ug/ml cyclohexamide. Cells were incubated withagonists (or vehicle control for the indicated times and reactions wereterminated by removal of medium, and washing with PBS. In experimentswith the antagonist W146, antagonist or vehicle was added to the cellsfor 30-45 min prior to agonist incubation. Cells were fixed in 3.7%paraformaldehyde for 10 min and mounted on coverslips using GelMountmounting media. Cells were scanned with an Olympus BX61 scanningconfocal fluorescence microscope. For detecting GFP, fluorescence wasexcited by using an argon laser at a wavelength of 488 nm, and theabsorbed wavelength was detected for 510-520 nm for GFP.Photomicrographs of ligand vs. vehicle were obtained using Metamorphsoftware and the images were assessed (in Photoshop) for the appearanceor not of vesicular S1P₁-GFP pattern of internalization, acharacteristic pattern adopted by most G protein-coupled receptorsfollowing ligand stimulation.

Immunoprecipitation and Immunoblotting for S1P₁-GFP andLigand-Stimulated S1P₁ Polyubiquitination

The effect of agonist-stimulated recruitment of poly-ubiquitin chains toS1P₁-GFP was analyzed by immunoprecipitation-immunoblotting experimentswith anti-GFP antibodies. Cells were seeded in 35 mm dishes and grown to˜95% confluence using regular growth medium. The growth medium wasreplaced by cs-FBS medium and the cells were incubated overnight. Drugsor vehicle (both made in cs-FBS medium) were incubated for the indicatedtimes. At the end of incubation, the monolayers were washed twice inice-cold PBS and lysates were obtained by incubation in RIPA buffer (50mM Tris-HCl, pH 7.5, 150 mM NaCl, 1 mM EDTA, 1% Nonidet P-40, 0.5%sodium deoxycholate, 0.1% SDS) plus protease inhibitors (Completetablets, Roche), and 1 mM NaVO₄, 1 mM NaF and 0.5M B-glycerol-phosphate.Cellular lysates were cleared by centrifugation (10,000×g, 15 min) andthe protein concentration of the lysate supernatants was determined bythe BCA (Pierce) method. Equal amounts of lysates (0.5-1 mg) wereincubated overnight at 4 C with a monoclonal GFP antibody (1 ug antibodyper 400 ug protein), followed by incubation with protein-A sepharosebeads (2 h, 4 C). The beads were recovered by centrifugation (10,000×g,1 min) and washing: 3×RIPA buffer: PBS (1:1) without protease inhibitorsand twice in PBS. The beads were suspended in 2× Laemli buffercontaining 2-mercaptoethanol, boiled for 10 min and proteins in thebeads separated by SDS-PAGE in Novex, 4-12% Tris-Glycine gels. Gels weresubsequently transferred to PVDF membranes, and probed overnight (4 C)with a polyclonal GFP antibody (1:10,000) for detection of S1P₁-GFPexpression or P4D1 (1:200-1:800) to detect theS1P₁-GFP-polyubiquitinated complex. Horseradish peroxidase-labeledantibodies were visualized by ECL chemiluminescence (AmershamBiosciences).

Agonists Stimulated Phosphorylation of S1P₁-GFP in HEK293 Cells.

Cells stably expressing the GFP-tagged human S1P₁ were metabolicallylabeled with P³² orthophosphate (80 μCi/ml, Perkin Elmer) for 2 h andsubsequently incubated with agonists at the indicated concentrations forthe indicated times at 37° C. Incubations were terminated by agonistremoval and PBS washing, and the receptor was immunoprecipitated with aGFP antibody from equal protein amounts of cellular lysates. Theimmunoprecipitated receptor was separated by SDS-PAGE, and incorporationof P³² onto the agonist-stimulated receptor was assessed byautoradiography (−80 C, 24 h exposure).

Internalization, Ubiquination and Phosphorylation of S1P1-GFP

During the course of the lead optimization studies, compounds SR-917,compound 32, and compound 236 were evaluated in depth in severalbiological studies. SR-917 is a known agonist of the S1P1 receptor,indexed in the NIH Molecular Libraries Small MoleculeRepositoryMLMSRCompound ID is 976135. It is commercially available fromChemBridge Screening Library.

Agonistic stimulation of the S1P1 receptor is modulated by receptordegradation. Ligand stimulation induces receptor phosphorylation,internalization, polyubiquination and degradation (Gonzalez-Cabrera, Hlaet al. 2007). Like AFD-R and SIP, stimulation with the syntheticcompound identified by high throughput screening, SR-917, results inS1P1-GFP internalization, protein phosphorylation and polyubiquination;see FIG. 1.

Compound 32 robustly induces internalization and polyubiquination with5178 and these effects are blocked by the S1P1 antagonist, W146R; seeFIG. 2.

Compound 236 like other compounds in the series, induces S1P1polyubiquination; see FIG. 3.

It was observed that S1P and the S1P1 specific agonist, SEW2897 inducelymphopenia (Wei, Rosen et al. 2005). SR-917 and compound 32, deliveredby gavage, did not induce lymphopenia in mice. Compound 236, at 10 mgpkby gavage, induced lymphopenia; see FIG. 4. Compound 236 is soluble inwater at 0.5 mg/mL and both i.v. and i.p. delivery induce lymphopenia(Sanna, Leaf).

Pharmacokinetics

From the initial mouse efficacy studies (FIG. 5) plasma levels ofCompound 236 at 5 hours were: 395/87.6 Mean/SD. Stability in hepaticmicrosomes for Compound 236 was species dependent. In human microsomes,the compound was very stable and moderately stable with rat. All wereNADPH dependent. In the presence of 1.8 mg/ml hepatic microsomes thehalf lives (minutes) are human stable, Mouse 50, Rat 16.

S1P1 polar amino acids essential for S1P mediated activation are not arerequired for S1P1 receptor activation by Compound 236. S1P requiresseveral polar amino acids (R120, E121 and R292) that line the ligandbinding pocket for complete activation (Jo, Sanna et al. 2005). The S1P1polar side chains of residues R120, E121 and R29 forms saltbridges withthe phosphate of S1P1 and the S1P can only minimally activate the R120A,E121A and R292A mutants. In contrast, wild-type S1P1 and R120A, E121Aand R292A mutant S1P1 receptors are indistinguishably activated byCompound 236 (FIG. 6).

Examples

The following compounds were synthesized and evaluated in bioassays asdescribed herein.

Synthetic Procedures

Solvents for extraction: ACS grade. Solvents for reaction: reagentgrade. Reagents: unless otherwise noted, from Alfa Aesar, Fisher andAldrich highest quality available. TLC: silica gel 60 F₂₅₄ aluminumplates, (whatman, type Al Sil G/UV, 250 μm layer); visualization by UVabsorption. Flash chromatography was performed on silica gel 60(0.40-0.63 mm, 230-440 mesh, EM Science). NMR: ¹H: δ values in ppm (TMSas internal standard); ¹³C: δ values in ppm (TMS as internal standard)

Reactions were monitored by LC/MS.

General Procedure to Reduce Aldehyde:

To a stirred suspension of aldehyde (1.0 equiv, 0.4M) and silica gel(catalytic) in ethanol at 0° C. was added NaBH₄ (⅓ equiv). The reactionwas allowed to warm up to room temperature and stirred for 2 h. TheSolvent was removed under reduced pressure and the product purified byCC in hexane/EtOAc (7:3).

General Procedure to Synthesized Amidoximes:

To a stirred suspension of Hydroxylamine hydrochloride (1.1 equiv) andNa₂CO₃ (1.1 equiv) in ethanol was added, in one portion, thecorresponding benzonitrile (1 equiv). The mixture was refluxed for 6 hfollowed by addition of NH₂OH.HCl (1.1 equiv) and Na₂CO₃ (1.1 equiv),the reaction was refluxed for additional 6 h. The suspension was cooledto room temperature and filtrated. The solid was washed with ethanol andthe organic phase concentrated under reduced pressure. The amidoximecrude was recrystallized from EtOAc/Hexanes and used without furtherpurification.

General Procedure to Synthesized Oxadiazoles:

To a stirring solution of 3,4-diethoxybenzoic acid (1 equiv, 0.2M) inDMF was added sequentially HOBt (1.3 equiv) and EDCI (1.3 equiv) at roomtemperature. The reaction was stirred for 20 min followed by addition,in a single portion, of the corresponding amidoxime (1.3 equiv, fromprevious step). The reaction was stirred for additional 30 min at roomtemperature and then heated to 90-95° C. for 8-14 h. The reaction wascooled to room temperature, diluted using a saturated solution of NaCland extracted with EtOAc (3×). The organic phase was dried over Na₂SO₄anhydrous and concentrated under reduced pressure. The product waspurified by C.C. using CH₂Cl₂:MeOH (9:1) to offer the diaryloxadiazolesin moderated yields.

General Procedure to Synthesize Amines.

To a stirred solution of benzylalcohol (1 equiv) and pyridine (1.1equiv) in CH₂Cl₂ at 0° C. was added drop wise SOCl₂ (1.1 equiv). Thereaction was warmed up to room temperature, stirred for additional 1 hand concentrated under reduced pressure. To a stirred solution of crudechloride in CH₂Cl₂ at 0° C. was added dropwise a solution of pyrrolidine(3 equiv) in CH₂Cl₂. The reaction was allowed to warm up to roomtemperature and stirred for 2 h. The organic phase was washed with waterand dried over Na₂SO₄ anhydrous. The crude was concentrated underreduced pressure and purified by column chromatography in DCM/MeOH toafford pyrrolidine derivatives in good yields.

Reduction of Indole-Derivatives.

To a stirred solution of Indole-core (1 equiv) in acetic acid at 13° C.was added slowly sodium cyanoborohydride (3 equiv). The reaction wasstirred for 2 h at 13° C. and monitored by TLC. After completion ofreaction the mixture was neutralize with 50% sodium hydroxide and theproduct extracted with ethyl acetate. The organic layer was dried overNa₂CO₃ and removed under reduced pressure. Indoline cores were purifiedby C.C. using CH₂Cl₂/MeOH (9:1) to offering quantitative yield.

Spectroscopic Data for Selected Compounds

¹H NMR (500 Hz, CDCl₃) δ: 8.80 (s, 2H), 8.03 (d, J=6.0 Hz, 2H), 7.80(dd, J=8.5, 2.0 Hz, 1H), 7.67 (d, J=2.0 Hz, 1H), 6.99 (d, J=8.5 Hz, 1H),4.23-4.16 (m, 4H), 1.53-1.44 (m, 6H). ¹³C NMR (125 Hz, CDCl₃) δ: 176.47,167.23, 152.99, 150.48, 148.88, 134.68, 122.16, 121.38, 120.31, 116.08,112.50, 112.25, 64.82, 64.60, 14.68, 14.60. MS. (M+1) 312.

¹H NMR (300 MHz, CDCl3) δ: 8.81 (brs, 2H), 8.06 (d, J=6.0 Hz, 2H), 7.32(s, 1H), 7.31 (s, 1H), 6.68 (t, J=2.4 Hz, 1H), 4.10 (q, J=6.9 Hz, 4H),1.45 (t, J=6.9 Hz, 6H); ¹³C NMR (75 MHz, CDCl3) δ: 176.68, 167.33,160.64, 150.24, 134.96, 125.12, 121.62, 121.59, 106.64, 106.41, 64.06,14.79. MS (M+1) 312

¹H NMR (500 Hz, CDCl₃) δ: 8.80 (s, 2H), 8.05 (d, J=5.0 Hz, 2H), 7.65 (d,J=3.0 Hz, 1H), 7.11-7.09 (dd, J=9.0, 3.0 Hz, 1H), 7.02 (d, J=9.0 Hz,1H), 4.18 (q, J=7.0 Hz, 2H), 4.08 (q, J=7.0 Hz, 2H), 1.52 (t, J=7.0 Hz,3H), 1.44 (t, J=7.0 Hz, 3H). ¹³C NMR (125 Hz, CDCl₃) δ: 175.92, 166.66,152.78, 152.44, 150.48, 134.73, 121.53, 116.36, 115.86, 115.40, 113.89,113.82, 113.69, 65.62, 64.30, 14.84, 14.80. MS. (M+1) 312.

¹HNMR (300 Hz, CDCl₃) δ: 8.81 (s, 2H), 8.04 (d, J=4.5 Hz, 2H), 7.82 (dd,J=8.4, 2.0 Hz, 1H), 7.66 (d, J=2.0 Hz, 1H), 7.00 (d, J=8.4 Hz, 1H), 4.22(q, J=7.0 Hz, 2H), 3.97 (s, 3H), 1.53 (t, J=7.0 Hz). ¹³C NMR (125 Hz,CDCl₃) δ: 176.53, 167.28, 153.48, 150.41, 148.75, 134.89, 122.18,116.30, 111.62, 111.36, 64.72, 56.20, 14.75. MS. (M+1) 298.

¹H NMR (500 Hz, CDCl₃) δ: 8.81 (s, 2H), 8.04 (d, J=6.0 Hz, 2H), 7.80 (d,J=7.5 Hz, 1H), 7.71-7.70 (m, 1H), 7.47 (t, J=8.5 Hz, 1H), 7.16 (d, J=8.5Hz, 1H), 4.16 (q, J=7.0 Hz, 2H), 1.48 (t, J=7.0 Hz, 3H). ¹³C NMR (125Hz, CDCl₃) δ: 176.48, 167.38, 159.39, 150.53, 134.50, 130.32, 129.40,124.82, 121.39, 120.46, 120.03, 115.92, 113.32, 63.88, 14.70. MS. (M+1)268.

¹H NMR (500 Hz, CDCl₃) δ: 8.81 (s, 2H), 8.05 (d, J=4.5 Hz, 2H), 7.73 (d,J=8.0 Hz, 1H), 7.60 (s, 1H), 7.31 (d, J=7.5 Hz, 1H), 3.96 (s, 3H), 2.31(s, 3H). ¹³C NMR (125 Hz, CDCl₃) δ: 176.71, 167.31, 158.13, 150.51,134.60, 133.06, 131.24, 130.10, 122.33, 121.41, 120.56, 118.84, 108.90,55.58, 16.62. MS. (M+1) 268.

¹H NMR (300 MHz, CDCl₃) δ: 8.84 (bs, 2H), 8.35 (d, J=4.5 Hz, 2H), 7.64(s, 1H), 6.63 (s, 1H), 4.03 (s, 3H), 4.01 (s, 3H), 3.96 (s, 3H). MS(M+1) 314.

¹H NMR (300 MHz, CDCl₃) δ: 8.80 (bs, 2H), 8.04 (bs, 2H), 7.78 (dd,J=8.4, 2.1 Hz, 1H), 7.65 (d, J=9.3, 1H), 6.97 (d, J=5.1 Hz, 1H),4.92-4.88 (m, 1H), 3.93 (s, 3H), 2.03-1.82 (m, 6H), 1.66-1.61 (m, 2H);¹³C NMR (75 MHz, CDCl₃) δ: 176.31, 167.01, 153.95, 150.20, 147.79,134.61, 121.75, 119.99, 115.94, 113.98, 113.96, 113.32, 111.35, 110.87,80.91, 55.91, 32.59, 23.93. MS (M+1) 338.

¹H NMR (300 MHz, CDCl₃) δ: 8.83 (d, J=5 Hz, 2H), 8.24 (d, J=5 Hz, 2H),8.15 (d, J=8.7 Hz, 2H), 7.05 (d, J=8.7 Hz, 2H), 3.91 (s, 3H). MS (M+1)254.

¹H NMR (300 MHz, CDCl₃) δ: 8.86 (bs, 2H), 8.34 (bs, 2H), 7.82 (dd,J=8.1, 1.7 Hz, 1H), 7.63 (d, J=1.7 Hz, 1H), 6.99 (d, J=8.1 Hz, 1H), 6.12(s, 2H). MS (M+1) 268.

4-(5-(3,4-diethoxyphenyl)-4H-1,2,4-triazol-3-yl)pyridine

Cold 4M HCl in dioxane (31.5 mmol, 8.87 mL) was added to a stirredsolution of 3,4-diethoxybenzonitrile (7.84 mmol, 1.5 g) in anhydrousMeOH (23.53 mmol, 954 μl) and anhydrous ether (4 mL) The reaction wasstirred at 0° C. for 1 h and then placed in the refrigerator (0-5° C.)for 48 h. To the mixture was bubbles N₂ to eliminate HCl andconcentrated under reduced pressure. To the crude was added etheranhydrous and the methyl 3,4-diethoxybenzimidate precipitate as paleorange solid in 63% yield (1.3 g). The product was used without furtherpurification.

To a stirred solution of the imidine (0.5 mmol, 130 mg) (freshlyliberated using a solution 1M of Na₂CO₃ and extracted with ether) inacetonitrile was added pyridine-4-carbohydrazide (0.55 mmol, 75.5 mg)and the reaction was reflux for 2 h. The mixture was concentrated underreduced pressure and the crude was heated at 180° C. for 2 h. Theproduct was purified by C.C. using CH₂Cl₂:MeOH (9:1) to offer theproduct as a with solid in 65% yield.

¹H NMR (400 MHz, CDCl₃) δ: 8.71 (bs, 2H), 8.11 (d, J=5.2 Hz, 2H), 7.60(s, 1H), 7.57 (d, J=8.4 Hz, 1H), 6.90 (d, J=8.4, 1H), 4.11 (q, J=6.8 Hz,2H), 4.07 (q, J=6.8 Hz, 2H), 1.45 (t, J=7.0 Hz, 3H), 1.40 (t, J=7.0 Hz,3H). ¹³C NMR (CDCl₃): 157.73, 150.89, 149.42, 149.14, 139.66, 121.29,120.56, 120.06, 119.68, 113.00, 111.53, 64.82, 64.72, 14.90, 14.86. MS(M+1) 311

2-(3,4-diethoxyphenyl)-5-(pyridin-4-yl)-1,3,4-oxadiazole (25)

To a stirred solution of 3,4-diethoxybenzoic acid (0.71 mmol, 150 mg) inCH₂Cl₂ was added SOCl₂ at room temperature and the reaction was refluxedfor 1.5 h. The mixture was concentrated under reduced pressure.

To a stirred suspension of Na₂CO₃ (1.42 mmol, 150.52 mg) andpyridine-4-carbohydrazide (0.71 mmol, 97 mg) in NMP (0.8 mL) was added asolution of 3,4-diethoxybenzoylchloride (prepare above) in NMP (0.8 mL)The reaction was stirred for 12 h at room temperature, poured to 20 mLof cold H₂O and filtered. The precipitated intermediate was dried invacuo. The solid was added to POCl₃ (5 mL) and heated to 70-72° C. for 6h. The solution was poured in an ice-water container and neutralizedwith a solution of NaOH (2M). The precipitated product was filtered andpurified by C.C. using CH₂Cl₂:MeOH (9:1) to yield the product in 67%yield (150 mg).

¹H NMR (400 MHz, CDCl₃) δ: 8.84 (bs, 2H), 7.99 (d, J=4.4 Hz, 2H), 7.67(dd, J=2.0, 8.4 Hz, 1H), 7.64 (d, J=2.0 Hz, 1H), 6.98 (d, J=8.4 Hz, 1H),4.20 (q, J=7.2 Hz, 2H), 4.18 (q, J=7.2 Hz, 2H), 1.51 (t, J=7.2 Hz, 3H),1.50 (t, J=7.2 Hz, 3H). ¹³C NMR (CDCl₃) δ: 165.81, 162.46, 152.51,150.84, 149.20, 131.52, 128.05, 120.97, 115.77, 112.78, 111.58, 65.05,64.80, 14.92, 14.85. MS (M+1)

3-(3,4-diethoxyphenyl)-5-(pyridin-4-yl)-1,2,4-oxadiazole

To a stirred solution of triethylamine (2 equiv) and NH₂OH.HCl (2 equiv)in ethanol was added 3,4-diethoxybenzonitrile (1 equiv) and the reactionwas reflux overnight. The reaction was concentrated under reducedpressure. The crude was dissolved in AcOEt and extracted with water. Theorganic portion was dried over Na₂SO₄ anhydrous and concentrated underreduced pressure. The crude was used without further purification.

To a stirred solution of isonicotinic acid (1 equiv) in DMF (in amicrowave vial) was added EDCI (1.3 equiv) and HOBt (1.3 equiv), thereaction was stirred for 5 min at room temperature followed by additionof the amidoxime (1.3 equiv) prepare above. The reaction was stirred foradditional 10 min, at room temperature then heated at 170° C. for 5 minin the microwave. The reaction was diluted using a saturated solution ofNaCl and extracted with EtOAc (3×). The organic phase was dried overNa₂SO₄ anhydrous and concentrated under reduced pressure. The productwas purified by C.C. using CH₂Cl₂:MeOH (9:1) to yield the oxadiazole in% yield.

¹H NMR (300 MHz, CDCl3) δ: 8.85 (d, J=5.4 Hz, 2H), 8.02 (d, J=6.0 Hz,2H), 7.71 (dd, J=8.1, 1.8 Hz, 1H), 7.62 (d, J=2.1 Hz, 1H), 6.95 (d,J=8.4 Hz, 1H), 4.19 (q, J=6.9 Hz, 2H), 4.14 (q, J=6.9 Hz, 2H), 1.50 (t,J=3.0 Hz, 3H), 1.46 (t, J=3.3 Hz, 3H); ¹³C NMR (75 MHz, CDCl3) δ:173.54, 16928, 151.64, 151.07, 148.91, 131.37, 121.48, 121.15, 118.75,112.74, 111.82, 64.78, 64.59, 14.87, 14.81; MS (M+1) 312.

¹H NMR (500 Hz, CDCl₃) δ: 8.63-8.61 (m, 1H), 7.99 (d, J=5 Hz, 1H), 7.80(dd, J=8.5, 2.0 Hz, 1H), 7.67 (d, J=1.5 Hz, 1H), 7.00 (d, J=8.5 Hz, 1H),4.23-4.17 (m, 4H), 2.68 (s, 3H), 1.52-1.49 (m, 6H). ¹³C NMR (125 Hz,CDCl₃) δ: 175.43, 167.82, 152.93, 152.24, 148.88, 147.62, 133.73,132.32, 123.10, 122.14, 116.13, 112.52, 112.29, 64.81, 64.60, 19.00,14.69, 14.61. MS. (M+1) 326.

¹H NMR (500 Hz, CDCl₃) δ: 8.84 (dt, J=3.0, 1.0 Hz, 1H), 8.76 (dd, J=7.5,1.0 Hz, 1H), 7.85-7.84 (m, 1H), 7.75 (d, J=2.0 Hz, 1H), 7.45-7.42 (m,1H), 6.98 (d, J=8.5 Hz, 1H), 4.22-4.16 (m, 4H), 1.51 (t, J=7.0 Hz, 6H).¹³CNMR (125 Hz) δ: 176.50, 168.61, 152.79, 150.35, 148.80, 146.62,136.99, 125.36, 123.20, 122.21, 116.33, 112.40, 64.81, 64.55, 14.70,14.60. MS. (M+1) 312.

¹H NMR (500 Hz, CDCl₃) δ: 9.40 (s, 1H), 8.76 (d, J=3.0 Hz, 1H), 8.45 (d,J=8.0 Hz, 1H), 7.82 (dd, J=8.5, 2.0 Hz, 1H), 7.69 (d, J=2.0 Hz, 1H),7.47-7.44 (m, 1H), 7.00 (d, J=8.5 Hz, 1H), 4.24-4.17 (m, 4H), 1.53-1.50(m, 6H). ¹³CNMR (125 Hz, CDCl₃) δ: 176.19, 166.82, 152.92, 151.68,148.89, 148.56, 134.90, 122.67, 122.15, 120.32, 116.23, 112.52, 112.29,64.84, 64.61, 14.70, 14.62. MS. (M+1) 312.

¹H NMR (500 Hz, CDCl₃) δ: 8.22 (d, J=4.5 Hz, 2H), 7.79 (dd, J=8.5, 2.0Hz, 1H), 7.66 (d, J=2.0 Hz, 1H), 7.37 (d, J=5.0 Hz, 1H), 7.26 (s, 1H),6.99 (d, J=8.5 Hz, 1H), 4.77-4.71 (m, 2H), 4.23-4.17 (m, 4H), 1.52-1.49(m, 6H). ¹³C NMR (125 Hz, CDCl₃) δ: 176.20, 167.51, 158.85, 152.90,148.86, 148.78, 136.32, 122.11, 116.22, 112.50, 112.25, 111.76, 106.58,64.82, 64.61, 14.70, 14.61. MS. (M+1) 327.

¹H NMR (300 Hz, CDCl₃) δ: 8.18-8.15 (m, 2H), 7.80 (dd, J1=1.8 Hz, J2=8.4Hz, 1H), 7.69 (d, J=3.1 Hz, 1H), 7.53-7.48 (m, 3H), 6.99 (d, J=8.4 Hz,1H), 4.23 (q, J=7.2 Hz, 2H), 4.19 (q, J=4.8 Hz, 2H), 1.53 (t, J=2.7 Hz,3H), 1.49 (t, J=4.2 Hz, 3H); MS (M+1) 311.

¹H NMR (300 MHz, CDCl₃) δ: 8.06 (dd, J=2.1, 8.7 Hz, 1H), 7.81 (dd,J=1.8, 8.4 Hz, 1H), 7.70 (d, J=2.1 Hz, 1H), 7.43-7.30 (m, 3H), 6.69 (d,J=8.7 Hz), 4.21 (q, J=6.9 Hz, 2H), 4.19 (q, J=6.9 Hz, 2H), 2.67 (s, 3H),1.51 (t, J=7.2 Hz, 6H); ¹³C NMR (75 MHz, CDCl3) δ: 174.76, 169.45,152.59, 148.80, 138.22, 131.33, 130.53, 130.49, 130.12, 126.45, 125.98,122.01, 116.69, 112.48, 112.25, 64.79, 64.09, 22.08, 14.75; MS 325 (M+1)

¹H NMR (300 MHz, CDCl₃) δ: 8.82 (bs, 2H), 8.02 (d, J=2.7, 2H), 7.93 (q,J=1.5 Hz, 1H), 7.47 (s, 5H); ¹³C NMR (75 MHz, CDCl₃) δ: 171.12, 167.81,150.86, 145.70, 135.09, 134.12, 133.14, 123.32, 129.04, 126.35, 126.33,121.67, 120.21, 105.04; MS 374 (M+1).

¹H NMR (300 MHz, CDCl₃) δ: 8.63 (brs, 2H), 7.95 (d, J=5.1 Hz, 1H), 7.912(t, J=1.5, 1H), 7.462 (s, 5H), 2.67 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ:170.06, 168.32, 152.51, 147.88, 145.63, 145.60, 134.93, 133.13, 132.69,129.26, 128.85, 126.40, 120.18, 105.01, 19.38; MS 388 (M+1)

H¹ NMR (400 MHz, CDCl₃) δ: 7.83 (d, J=7.6 Hz, 1H), 7.79 (dd, J=2, 8.4Hz, 1H), 7.68 (d, J=2 Hz, 1H), 7.32 (t, J=8 Hz, 1H), 6.98 (d, J=8.0 Hz,1H), 4.78 (s, 2H) 4.18 (q, J=7.2 Hz, 4H), 2.55 (s, 3H), 1.50 (t, 6.8 Hz,6H). ¹³C NMR (CDCl₃) δ: 175.2, 169.8, 152.9, 149.0, 140.2, 136.3, 130.0,129.9, 127.6, 126.1, 122.2, 116.7, 112.7, 112.4, 65.0, 64.8, 63.8, 16.4,14.9. MI (M+1)

¹H NMR (500 MHz, CDCl₃) δ: 8.05 (d, J=7.5 Hz, 1H), 7.80 (dd, J=8.0 Hz,2.0 Hz, 1H), 7.68 (d, J=2.0 Hz, 1H), 7.31-7.29 (m, 2H), 6.99 (d, J=8.5Hz, 1H), 4.73 (s, 2H), 4.21-4.18 (m, 4H), 2.66 (s, 3H), 1.52 (dt, J=7.0Hz, 1 Hz, 6H). ¹³C NMR (125 MHz, CDCl₃) δ: 174.70, 169.17, 152.59,148.78, 143.23, 138.45, 130.34, 129.57, 125.56, 124.18, 121.18, 121.99,116.60, 112.51, 112.32, 64.78, 64.57, 22.07, 14.69, 14.61. MS. (M+1)355.

¹H NMR (500 MHz, CDCl₃) δ: 7.968-7.94 (m, 2H), 7.79 (dd, J=8.5 Hz, 1.5Hz, 1H), 7.68 (d, J=2.0 Hz, 1H), 7.50 (d, J=8.0 Hz, 1H), 6.98 (d, J=8.0Hz, 1H), 4.75 (s, 2H), 4.23-4.16 (m, 4H), 2.40 (s, 3H), 1.52 (dt, J=7.0Hz, 1 Hz, 6H). ¹³C NMR (125 MHz, CDCl₃) δ: 175.62, 168.61, 164.61,152.61, 148.77, 141.82, 136.39, 129.06, 127.47, 126.14, 125.20, 122.0,116.59, 112.47, 112.28, 64.78, 64.56, 63.05, 18.57, 14.69, 14.61. MS.(M+1) 355.

1H NMR (300 MHz, CDCl₃) δ: 8.06 (d, J=8.1 Hz, 2H), 7.76 (dd, J=1.5, 9.9Hz, 1H), 7.66 (d, J=1.8 Hz, 1H), 7.34 (d, J=8.1 Hz, 2H), 6.96 (d, J=8.4Hz, 1H), 4.21 (q, J=7.2 Hz, 2H), 4.16 (q, J=6.9 Hz, 2H), 3.88 (t, J=6.6Hz, 2H), 2.91 (t, J=6.6 Hz, 2H), 1.51 (t, J=1.5, 3H), 1.48 (t, J=1.2 Hz,3H); ¹³C NMR (75 MHz, CDCl₃) δ: 175.54, 168.52, 152.49, 148.64, 141.98,132.14, 129.72, 127.59, 125.17, 121.93, 116.46, 112.31, 112.07, 64.68,64.47, 63.25, 39.07, 14.64. MS 355 (M+1)

H¹ NMR (400 MHz, CDCl₃) δ: 8.11 (s, 1H), 8.05 (d, J=7.6 Hz, 1H), 7.79(dd, J=2.0, 8.4 Hz, 1H), 7.55 (d, J=7.6 Hz, 1H), 7.46 (t, J=7.6 Hz, 1H),6.98 (d, J=8.4 Hz, 1H), 4.22 (q, J=7.2 Hz, 2H), 4.18 (q, J=7.2 Hz, 2H),3.74 (s, 2H), 2.60 (s, 4H), 1.82 (s, 4H), 1.52 (t, J=7.0 Hz, 3H), 1.50(t, J=7.0 Hz, 3H). ¹³C NMR (CDCl₃) δ: 175.87, 169.02, 152.80, 148.98,132.02, 129.09, 128.21, 127.27, 126.51, 122.20, 116.85, 112.64, 112.44,64.99, 64.77, 60.47, 54.31, 23.69, 14.93, 14.85. MI (M+1) 394.

¹H NMR (400 MHz, CDCl₃) δ: 8.07 (d, J=8.4 Hz, 2H), 7.74 (dd, J=1.6, 8.4Hz, 1H), 1.64 (d, J=1.6 Hz, 1H), 7.44 (d, J=8.0 Hz, 2H), 6.92 (d, J=8.4Hz, 1H), 4.17 (q, J=7.2 Hz, 2H), 4.12 (q, J=7.2 Hz, 2H), 3.68 (s, 2H),2.54 (s, 4H), 1.77 (s, 4H), 1.47 (t, J=7.0 Hz, 3H), 1.45 (t, J=7.0 Hz,3H). ¹³C NMR (CDCl₃) δ: 175.68, 168.72, 152.65, 148.82, 142.13, 129.42,127.54, 125.95, 122.05, 116.67, 112.50, 112.27, 64.82, 64.61, 60.31,54.14, 23.51, 14.79, 14.71. MI (M+1) 394.

H¹ NMR (400 MHz, CDCl₃) δ: 7.79 (dd, J=2.0, 8.4 Hz, 1H), 7.77 (d, J=7.6Hz, 1H), 7.68 (d, J=2.0 Hz, 1H), 7.50 (d, J=7.6 Hz, 1H), 7.28 (t, J=7.6Hz, 1H), 6.98 (d, J=8.4 Hz, 1H), 4.20 (q, J=7.0 Hz, 2H), 4.19 (q, J=7.0Hz, 2H), 3.72 (s, 2H), 2.59 (s, 4H), 1.80 (s, 4H), 1.50 (t, J=7.0 Hz,6H). ¹³C NMR (CDCl₃) δ: 175.06, 170.12, 152.77, 148.98, 137.18, 131.98,129.40, 127.50, 125.75, 122.17, 116.84, 112.66, 112.40, 64.95, 64.77,58.51, 54.42, 23.74, 16.80, 14.91, 14.84.

¹H NMR (500 Hz, CDCl₃) δ: 8.01 (d, J=7.5 Hz, 1H), 7.81 (dd, J=8.5 Hz, 2Hz, 1H), 7.69 (d, J=2 Hz, 1H), 7.32-7.31 (m, 2H), 6.99 (d, J=8.5 Hz,1H), 4.23-4.17 (m, 4H), 3.67 (s, 2H), 2.65 (s, 3H), 2.56 (s, 4H),1.83-1.80 (m, 4H), 1.52-1.49 (m, 6H). ¹³C NMR (125 Hz, CDCl₃) δ: 174.63,169.33, 152.56, 148.80, 138.15, 131.78, 131.07, 126.46, 125.11, 121.96,116.72, 112.54, 112.35, 64.78, 64.7, 60.32, 54.17, 23.46, 22.00, 14.70,14.63. MS. (M+1) 408.

¹H NMR (500 MHz, CDCl₃) δ: 7.94-7.93 (m, 2H), 7.80 (dd, J=8.5 Hz, 2.0Hz, 1H), 7.69 (d, J=2.0 Hz, 1H), 7.47 (d, J=8.0 Hz, 1H), 6.98 (d, J=8.5Hz, 1H), 4.24-4.15 (m, 4H), 3.65 (s, 2H), 2.56-2.54 (m, 4H), 2.44 (s,3H), 1.80-1.78 (m, 4H), 1.52 (q, J=7.0 Hz, 6H). ¹³C NMR (125 MHz, CDCl₃)δ: 175.49, 168.80, 152.54, 148.76, 140.88, 137.34, 129.51, 128.95,125.39, 124.82, 121.94, 116.71, 112.46, 112.29, 64.76, 64.53, 57.82,54.29, 23.55, 19.14, 14.68, 14.60. MS. (M+1) 408.

¹H NMR (300 MHz, CDCl3) δ: 8.06 (d, J=8.0 Hz, 2H), 7.72 (dd, J=8.4, 2.0,1H), 7.61 (d, J=2.0 Hz, 1H), 7.33 (d, J=8.4, 2H), 6.92 (d, J=8.4, 1H),4.16 (q, J=6.8, 2H), 4.11 (q, J=6.8, 2H), 3.30-3.22 (m, 4H), 2.74-2.69(m, 2H), 2.21-2.19 (m, 2H), 2.02 (m, 2H), 1.47 (t, J=10 Hz, 3H), 1.43(t, J=3.6, 3H); MS 408 (M+1).

H¹ NMR (400 MHz, CDCl₃) δ: 8.01 (d, J=7.2 Hz, 1H), 7.81 (dd, J=8.4, 2.0Hz, 1H), 7.52 (s, 1H), 7.52 (d, J=8.0 Hz, 1H), 7.34 (s, 1H), 7.28 (t,J=8.0 Hz, 1H), 7.23 (s, 1H), 6.96 (d, J=8.4 Hz, 1H), 4.18 (q, J=6.8 Hz,2H), 4.16 (q, J=6.8 Hz, 2H), 1.47 (t, J=6.8 Hz, 3H), 1.46 (t, J=6.8 Hz,3H). ¹³C NMR (CDCl₃) δ: 175.0, 169.5, 152.6, 148.9 (2), 125.7, 122.2,121.8, 121.7, 121.3, 121.2, 117.0, 114.4, 114.3, 112.7, 112.5; MI (M+1)350.

¹H NMR (300 MHz, CDCl3) δ: 7.78 (dd, J=8.4, 2.1 Hz, 1H), 7.68 (d, J=1.8Hz, 1H), 7.55 (d, J=7.8 Hz, 1H), 7.16 (t, J=7.5 Hz, 1H), 6.97 (d, J=7.5Hz, 1H), 6.76 (d, J=7.5 Hz, 1H), 4.21 (q, J=6.9 Hz, 2H), 4.16 (q, J=6.9Hz, 2H), 3.65 (brs, 2H), 3.46 (t, J=8.1 Hz, 2H), 1.52 (t, J=3.1 Hz, 3H),1.48 (t, J=3.3 Hz, 3H); ¹³C NMR (75 MHz, CDCl3) δ: 175.05, 169.06,152.62, 148.84, 127.84, 123.67, 122.09, 118.90, 116.83, 112.53, 112.32,111.60, 64.86, 64.67, 47.29, 31.41, 14.85, 14.78. MS 352 (M+1)

¹H NMR (500 MHz, CDCl₃) δ: 7.80 (dd, J=8.5, 2 Hz, 1H), 7.69 (d, J=2.0Hz, 1H), 7.45 (d, J=7.5 Hz, 1H), 7.14 (d, J=8.0 Hz, 2H), 6.97 (d, J=8.0Hz, 1H), 4.24-4.15 (m, 4H), 3.98-3.95 (m, 1H), 3.43 (t, J=8.5 Hz, 2H),3.01 (t, J=8.5 Hz, 2H), 1.52 (q, J=7.0 Hz, 6H), 1.20 (d, J=6.5 Hz, 6H).¹³C NMR (125 MHz, CDCl₃) δ: 175.24, 169.48, 152.4, 148.74, 133.96,126.11, 124.39, 121.93, 116.92, 112.46, 112.35, 105.03, 64.77, 64.52,4.42, 28.42, 28.10, 18.18, 14.69, 14.60. MS. (M+1) 352.

¹H NMR (500 MHz, CDCl₃) δ: 8.56 (s, 1H), 8.51 (s, 1H), 8.01 (dd, J=8.5Hz, 1.5 Hz, 1H), 7.83 (dd, J=8.5 Hz, 2.0 Hz, 1H), 7.73 (d, J=1.5 Hz,1H), 7.45 (d, J=8.5 Hz, 1H), 7.27-7.26 (m, 1H), 7.00 (d, J=8.5 Hz, 1H),6.66-6.65 (m, 1H), 4.24-4.17 (m, 4H), 1.52-1.48 (m, 6H). ¹³C NMR (125MHz, CDCl₃) δ: 175.26, 169.79, 152.44, 148.75, 137.33, 127.93, 125.27,121.94, 121.27, 120.94, 118.77, 116.96, 112.51, 112.34, 111.43, 103.56,64.78, 64.56, 14.70, 14.62. MS. (M+1) 350.

¹H NMR (500 MHz, CDCl₃) δ: 7.86-7.82 (m, 2H), 7.78 (dd, J=8.0 Hz, 2 Hz,1H), 7.68 (d, J=2.0 Hz, 1H), 6.98 (d, J=8.5 Hz, 1H), 6.69 (d, J=8.0 Hz,1H), 4.23-4.16 (m, 5H), 3.67 (t, J=8.5 Hz, 2H), 3.18 (t, J=8.0 Hz, 2H),1.52-1.48 (m, 6H). ¹³C NMR (125 MHz, CDCl₃) δ: 175.00, 169.08, 154.04,152.40, 148.73, 129.62, 127.89, 123.85, 121.87, 117.04, 116.98, 112.48,112.32, 105.92, 64.76, 64.54, 47.28, 29.23, 14.71, 14.63.

MS. (M+1) 352

¹H NMR (300 MHz, CDCl3) δ: 7.78 (dd, J=8.4, 2.1 Hz, 1H), 7.68 (d, J=2.1,1H), 7.46 (d, J=7.8 Hz, 1H), 7.20 (t, J=9.6 Hz, 1H), 6.96 (d, J=8.4 Hz,1H), 6.60 (d, J=7.8 Hz, 1H), 4.20 (q, J=7.2 Hz, 2H), 4.17 (q, J=7.2 Hz,2H), 3.55 (t, J=1.8 Hz, 2H), 3.40 (t, J=7.2 Hz, 2H), 3.29 (t, J=7.2 Hz,2H), 2.73 (t, J=7.8 Hz, 2H), 2.60 (q, J=7.2 Hz, 4H), 1.51 (t, J=2.1 Hz,3H), 1.49 (t, J=1.8 Hz, 3H), 1.09 (t, J=7.2 Hz, 6H). ¹³C NMR (CDCl3) δ:174.30, 168.39, 152.52, 151.93, 148.17, 129.32, 127.33, 122.70, 121.40,116.75, 116.21, 111.87, 107.94, 104.24, 64.15, 52.82, 49.53, 46.92,29.54, 14.15, 11.03; MS 451 (M+1).

¹H NMR (300 MHz, CDCl3) δ: 8.95 (d, J=8.4 Hz, 1H), 8.33 (d, J=7.2 Hz,1H), 8.02 (d, J=8.4 Hz, 1H), 7.94 (d, J=8.1 Hz, 1H), 7.86 (d, J=8.4 Hz,1H), 7.74 (s, 1H), 7.65-7.54 (m, 3H), 7.0 (d, J=8.4 Hz, 1H), 4.23 (q,J=6.9 Hz, 2H), 4.20 (q, J=7.2 Hz, 2H), 1.52 (t, J=7.2 Hz, 6H); ¹³C NMR(75 MHz, CDCl3) δ: 174.23, 168.57, 152.00, 148.15, 133.22, 131.00,130.08, 128.65, 127.94, 126.82, 125.64, 124.44, 123.51, 121.44, 115.92,111.81, 111.61, 64.13, 14.07. MS (M+23) 383.

¹H NMR (500 MHz, CDCl₃) δ: 9.03 (d, J=8.5 Hz, 1H), 8.80 (d, J=5.5 Hz,1H), 7.94-7.90 (m, 2H), 7.84-7.71 (m, 4H), 7.01 (d, J=8.5 Hz, 1H),4.23-4.17 (m, 4H), 1.52-1.49 (m, 6H). ¹³C NMR (125 Hz, CDCl₃) δ: 175.95,168.38, 152.91, 148.84, 146.36, 142.37, 136.93, 130.70, 128.68, 127.20,127.08, 123.04, 122.38, 122.37, 116.22, 112.62, 112.45, 64.86, 64.58,14.72, 14.62. MS. (M+1) 362.

¹H NMR (500 MHz, CDCl₃) δ: 7.83 (d, J=7.5 Hz, 1H), 7.80 (dd, J=8.5 Hz,2.0 Hz, 1H), 7.68 (d, J=2.0 Hz, 1H), 7.50 (d, J=7.0 Hz, 1H), 7.33 (t,J=7.5 Hz, 1H), 6.99 (d, J=8.5 Hz, 1H), 4.22-4.17 (m, 4H), 3.95 (s, 2H),3.73-3.70 (m, 2H), 2.92-2.90 (m, 2H), 2.60 (s, 3H), 2.47 (s, 2H),1.52-1.49 (m, 6H). ¹³C NMR (125 MHz, CDCl₃) δ: 174.95, 169.69, 152.68,148.84, 137.99, 136.65, 132.75, 131.30, 129.76, 127.70, 125.93, 122.02,116.58, 112.32, 64.80, 64.59, 60.51, 51.27, 50.68, 14.70, 14.63. MS.(M+1) 398.

¹H NMR (500 MHz, CDCl₃) δ: 8.05 (d, J=8.0 Hz, 1H), 7.80 (dd, J=5.0 Hz,2.0 Hz, 1H), 7.68 (d, J=2.0 Hz, 1H), 7.32-7.23 (m, 2H), 6.99 (d, J=8.5Hz, 1H), 4.28-4.17 (m, 4H), 3.89-3.84 (m, 2H), 3.72-3.69 (m, 2H), 2.86(s, 2H), 2.66 (s, 3H), 2.54-2.48 (m, 3H), 1.52 (dt, J=7.0 Hz, 1 Hz, 6H).¹³C NMR (125 MHz, CDCl₃) δ: 174.72, 169.16, 152.63, 148.82, 138.52,132.63, 131.27, 130.41, 129.78, 125.85, 125.61, 121.99, 116.65, 112.56,112.37, 64.80, 64.59, 22.06, 14.71, 14.63. MS. (M+1) 398.

1-hydroxy-2,3-dihydro-1H-indene-4-carbonitrile

To a stirred suspension of 1-oxo-2,3-dihydro-1H-indene-4-carbonitrile(1.0 equiv, 0.4M) and silica gel (catalytic) in ethanol at 0° C. wasadded NaBH₄ (⅓ equiv). The reaction was allowed to warm up to roomtemperature and stirred for 2 h. The Solvent was removed under reducedpressure and the product purified by CC in hexane/EtOAc (5:5) to offer1-hydroxy-2,3-dihydro-1H-indene-4-carbonitrile in 80% yield.

¹H NMR (400 MHz, CDCl₃) δ: 8.10 (d, J=7.6, 1H), 7.78 (dd, J=1.6, 8 Hz,1H), 7.67 (d, J=1.6 Hz, 1H), 7.56 (d, J=7.6 Hz, 1H), 7.39 (t, J=7.6,1H), 6.97 (d, J=8.0 Hz, 1H), 5.29 (t, J=6.4 Hz, 1H), 4.19 (q, J=7.2,2H), 4.18 (q, J=7.2, 2H), 3.51-4.43 (m, 1H), 3.22-3.14 (m, 1H),2.59-2.51 (m, 1H), 2.04-1.97 (m, 1H), 1.5 (t, J=7.2, 3H), 1.49 (t,J=7.2, 3H): ¹³C NMR (CDCl₃) δ: 175.2, 168.9, 152.8, 148.9, 146.6, 143.3,128.9, 127.4, 127.0, 123.8, 122.2, 116.7, 112.7, 112.4, 76.2, 64.9,64.8, 35.7, 31.5, 14.9, 14.8: MI (M+1) 367

4-(5-(3,4-diethoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-one

To a suspension of PCC (1.5 equiv.) and powdered molecular sieves (3 Å,one-half the weight of PCC) in dry CH₂Cl₂ was added the benzylic alcohol(1 equiv. prepared in previous step) at 0° C. The reaction mixture wasstirred overnight at room temperature and concentrated under reducedpressure. To the residue was added Et₂O-EtOAc (1:1) and the slurry wasstirred and filtered through a pad of Celite. The residue was washed 4times with Et₂O-EtOAc (1:1). The filtrate was concentrated under reducedpressure and the product purified by CC offering the ketone in 70%yield.

¹H NMR (500 MHz, CDCl₃) δ: 8.48 (dd, J=8.0 Hz, 1.5 Hz, 1H), 7.91 (d,J=7.5 Hz, 1H), 7.81 (dd, J=8.5 Hz, 2.0 Hz, 1H), 7.68 (d, J=2.0 Hz, 1H),7.56 (t, J=7.5 Hz, 1H), 6.99 (d, J=8.5 Hz, 1H), 4.24-4.17 (m, 4H),3.55-3.53 (m, 2H), 2.79-2.77 (m, 2H), 1.53-1.49 (m, 6H). ¹³C NMR (125MHz, CDCl₃) δ: 206.62, 175.32, 167.79, 154.40, 152.86, 148.86, 138.22,134.63, 127.72, 126.00, 125.55, 122.10, 116.32, 112.55, 112.36, 64.82,64.60, 36.25, 27.61, 14.70, 14.61. MS. (M+1) 365.

Amination Procedure.

A solution of alcohol (1 equiv), at 0° C., was treated with SOCl₂ (1.1equiv) and pyridine (1.1 equiv) in CH₂Cl₂. The reaction was stirred atroom temperature for 2 h. The reaction was diluted with CH₂Cl₂ andwashed with NaHCO₃ (2×). The organic phase was dried over sodium sulfateand concentrated under reduced pressure. The crude was dissolved in DMFand treated with the corresponding amine (2 equiv) and DIPEA (2.0equiv). The reaction was stirred at 50° C. for 48 h. The reaction wasdiluted with H₂O and the product extracted with EtOAc (3×). The productwas purified by C.C. using CH₂Cl₂/MeOH (9:1) to offeramino-diaryloxadiazoles in moderated yields.

¹H NMR (500 MHz, CDCl₃) δ: 8.12 (d, J=7.5 Hz, 1H), 7.79 (dd, J=8.5, 2.0Hz, 1H), 7.68 (d, J=2.0 Hz, 1H), 7.63 (d, J=7.5 Hz, 1H), 7.40-7.37 (m,1H), 4.49-4.47 (m, 1H), 4.23-4.16 (m, 4H), 3.78-3.70 (m, 1H), 3.53-3.46(m, 1H), 3.29-3.22 (m, 1H), 2.96-2.94 (m, 4H), 2.56-2.50 (m, 1H),2.09-2.03 (m, 1H), 1.52-1.49 (m, 6H). ¹³C NMR (125 Hz): 175.03, 168.66,152.71, 148.87, 143.76, 128.71, 127.11, 123.89, 122.04, 116.67, 112.63,112.49, 64.84, 64.61, 62.70, 60.34, 47.98, 31.90, 29.69, 14.72, 14.64.MS. (M+1) 410.

¹H NMR (400 MHz, CDCl₃) δ: 8.10 (d, J=7.6 Hz, 1H), 7.79 (dd, J=8.5, 2.0Hz, 1H), 7.69 (d, J=2.0 Hz, 1H), 7.55 (d, J=7.6 Hz, 1H), 7.38 (t, J=7.6Hz, 1H), 6.99 (d, J=8.4 Hz, 1H), 4.44 (t, J=6.8 Hz, 1H), 4.24-4.16 (m,4H), 3.42-3.34 (m, 1H), 3.27-3.19 (m, 1H), 3.28 (s, 6H), 2.19-2.12 (m,4H), 1.53-1.48 (m, 6H). ¹³C NMR (75 MHz, CDCl₃): 174.09, 168.87, 152.58,148.77, 143.88, 128.27, 127.91, 126.79, 123.47, 121.98, 116.67, 114.84,112.49, 112.31, 69.67, 64.77, 64.56, 40.66, 32.40, 23.05, 14.70, 14.62.MS. (M+1) 394.

2-(3,4-diethoxyphenyl)-5-(pyridin-4-yl)-1,3,4-oxadiazole

To a stirred solution of 3,4-diethoxybenzoic acid (0.71 mmol, 150 mg) inCH₂Cl₂ was added SOCl₂ at room temperature; the reaction was refluxedfor 1.5 h and the mixture concentrated under reduced pressure to yield3,4-diethoxybenzoylchloride quantitatively. To a stirred suspension ofNa₂CO₃ (1.42 mmol, 150.52 mg) and pyridine-4-carbohydrazide (0.71 mmol,97 mg) in NMP (0.8 mL) was added a solution of the3,4-diethoxybenzoylchloride in NMP (0.8 mL) and the reaction was stirredfor 12 h at room temperature. The mixture was poured into 20 mL of coldH₂O and filtered. The precipitated intermediate was dried in vacuum. Thesolid was added to POCl₃ (5 mL) and heated to 70-72° C. for 6 h. Thesolution was poured into an ice-water container and neutralized with asolution of NaOH (2M). The precipitated product was filtered andpurified by column chromatography using CH₂Cl₂:MeOH (9:1) to yield theproduct as white solid in 67% yield (150 mg). ¹H NMR (400 MHz, CDCl₃): δ8.84 (bs, 2H), 7.99 (d, J=4.4 Hz, 2H), 7.67 (dd, J1=2.0, J2=8.4 Hz, 1H),7.64 (d, J=2.0 Hz, 1H), 6.98 (d, J=8.4 Hz, 1H), 4.20 (q, J=7.2 Hz, 2H),4.18 (q, J=7.2 Hz, 2H), 1.51 (t, J=7.2 Hz, 3H), 1.50 (t, J=7.2 Hz, 3H);¹³C NMR (100 MHz, CDCl₃): δ 165.81, 162.46, 152.51, 150.84, 149.20,131.52, 128.05, 120.97, 115.77, 112.78, 111.58, 65.05, 64.80, 14.92,14.85. MS (EI) m/z: 312 (M⁺), HRMS (EI) for C₁₇H₁₇N₃O₃ (M⁺): calcd312.1343. found 312.1350.

4-(5-(3,4-diethoxyphenyl)-4H-1,2,4-triazol-3-yl)pyridine

Cold 4M HCl in dioxane (31.5 mmol, 8.87 mL) was added to a stirredsolution of 3,4-diethoxybenzonitrile (7.84 mmol, 1.5 g) in anhydrousMeOH (23.53 mmol, 954 μl) and anhydrous ether (4 mL) The reaction wasstirred at 0° C. for 1 h and then placed in the refrigerator (0-5° C.)for 48 h. The mixture was bubbled with N₂ to eliminate HCl andconcentrated under reduced pressure. To the crude was added anhydrousether and the methyl 3,4-diethoxybenzimidate salt precipitated as paleorange solid in 63% yield (1.3 g). The product was used without furtherpurification. To a stirred solution of the imidine (0.5 mmol, 130 mg)(freshly liberated from the imidate salt using a solution 1M of Na₂CO₃and extracted with ether) in acetonitrile was addedpyridine-4-carbohydrazide (0.55 mmol, 75.5 mg) and the reaction wasrefluxed for 2 h. The mixture was concentrated under reduced pressureand the crude was heated at 180° C. for 2 h. The product was purified bycolumn chromatography using CH₂Cl₂:MeOH (9:1) to offer the product as awhite solid in 65% yield (100 mg, 0.32 mmol). ¹H NMR (400 MHz, CDCl₃): δ8.71 (bs, 2H), 8.11 (d, J=5.2 Hz, 2H), 7.60 (s, 1H), 7.57 (d, J=8.4 Hz,1H), 6.90 (d, J=8.4, 1H), 4.11 (q, J=6.8 Hz, 2H), 4.07 (q, J=6.8 Hz,2H), 1.45 (t, J=7.0 Hz, 3H), 1.40 (t, J=7.0 Hz, 3H); ¹³C NMR (100 MHz,CDCl₃): δ 157.73, 150.89, 149.42, 149.14, 139.66, 121.29, 120.56,120.06, 119.68, 113.00, 111.53, 64.82, 64.72, 14.90, 14.86. MS (EI) m/z:311 (M⁺), HRMS (EI) for C₁₇H₁₈N₄O₂ (M⁺): calcd 311.1502. found 311.1506.

4-[5-(4-Phenyl-5-trifluoromethyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-pyridine

In a round bottom flask, a stirring solution of 3,4-diethoxybenzoic acid(100 mg, 0.3673 mmol) in DMF (1.8 mL) was treated sequentially with HOBt(64 mg, 0.48 mmol)) and EDCI (91 mg, 0.48 mmol) at room temperature. Thereaction was stirred for 20 min followed by addition, in a singleportion of N′-hydroxyisonicotinimidamide (66 mg, 0.48 mmol). Thereaction was stirred for additional 30 min at room temperature and thenheated to 90-95° C. for 10 h. The reaction was cooled to roomtemperature, diluted with a saturated solution of NaCl and extractedwith EtOAc (3×50 mL) The organic phase was dried over Na₂SO₄ anhydrousand concentrated under reduced pressure. The product was purified bycolumn chromatography using CH₂Cl₂:MeOH (9:1) to offer the product as apale yellow solid in 56% yield (78 mg). ¹H NMR (300 MHz, CDCl₃): δ 8.82(bs, 2H), 8.02 (d, J=2.7, 2H), 7.93 (q, J=1.5 Hz, 1H), 7.47 (s, 5H); ¹³CNMR (75 MHz, CDCl₃): δ 171.12, 167.81, 150.86, 145.70, 135.09, 134.12,133.14, 123.32, 129.04, 126.35, 126.33, 121.67, 120.21, 105.04. MS (EI)m/z: 374 (M⁺), HRMS (EI) for C₁₈H₁₀F₃N₃SO (M⁺): calcd 374.0569. found374.0579.

6-(5-(3,4-diethoxyphenyl)-1,2,4-oxadiazol-3-yl)indolin-2-one

To a solution of 2-oxoindoline-4-carbonitrile (500 mg, 3.16 mmol) inethanol were added cautiously hydroxylamine hydrochloride (286 mg, 4.11mmol) and potassium bicarbonate (411 mg, 4.11 mmol). The reactionmixture was refluxed for 20 h under nitrogen atmosphere. The mixture wascooled to room temperature and the solid was filtered. The organicsolvent was concentrated under reduced pressure and theN′-hydroxyimidamide was used in the next step without furtherpurification.

To a stirred solution of 3,4-diethoxybenzoic acid (73 mg, 0.35 mmol) in1,4-dioxane was added EDCI (87 mg, 0.45 mmol) and HOBt (62 mg, 0.45mmol), the reaction was stirred 20 min at room temperature. To thereaction was added the N′-hydroxyimidamide (87 mg, 0.45 mmol) and themixture was stirred for 30 min at room temperature followed by 16 h at95° C. The reaction was concentrated under reduced pressure, dilutedwith EtOAc (80 ml) and washed with brine (2×30 ml). The organic layerwas dried over Na₂SO₄ and concentrated under reduced pressure. The crudewas purified by column chromatography using CH₂Cl₂:MeOH (9:1) to offerthe product as a pale yellow solid 50% yield (64 mg, 0.175 mmol). MS(EI) m/z: 366 (M⁺)

5-(3,4-diethoxyphenyl)-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1,2,4-oxadiazole

To a solution of 4-cyano-7-azaindole (1 g, 7 mmol) in methanol (30 mL)were added cautiously hydroxylamine hydrochloride (632 mg, 9.1 mmol) andsodium carbonate (964 mg, 9.1 mmol). The reaction mixture was reflux for6 h under nitrogen atmosphere and hydroxylamine hydrochloride (632 mg,9.1 mmol) and sodium carbonate (964 mg, 9.1 mmol) were added, thereaction was reflux for additional 14 h. The mixture was cooled to roomtemperature and the solid was filtered. The organic solvent wasconcentrated under reduced pressure and the crude was recrystallizedfrom ethanol to yield 200 mg of N′-hydroxyimidamide.

To a stirred solution of 3,4-diethoxybenzoic acid (50 mg, 0.24 mmol) inDMF was added EDCI (59 mg, 0.31 mmol) and HOBt (41 mg, 0.31 mmol), thereaction was stirred 20 min at room temperature. To the reaction wasadded the N′-hydroxyimidamide (54 mg, 0.31 mmol) and the mixture wasstirred for 30 min at room temperature followed by 16 h at 95° C. Thereaction was concentrated under reduced pressure, diluted with EtOAc (80ml) and washed with a saturated solution of NaHCO₃ (2×30 ml) and brine(50 ml). The organic layer was dried over Na₂SO₄ and concentrated underreduced pressure. The crude was purified by column chromatography usingCH₂Cl₂:MeOH (9:1) to offer the product as a brown solid in 5% yield (4mg, 0.01 mmol). MS (EI) m/z: 351 (M⁺)

3-(1H-indol-5-yl)-5-(4-phenyl-5-(trifluoromethyl)thiophen-2-yl)-1,2,4-oxadiazole

To a solution of 1H-indole-5-carbonitrile (2 g, 14.06 mmol) in ethanolunder reflux were added, in three equal portions, hydroxylaminehydrochloride (4.88 g, 70.3 mmol) and potassium bicarbonate (7.04 g,70.3 mmol), the reaction was reflux for 16 h. The mixture was cooled toroom temperature and the solid was filtered. The organic solvent wasconcentrated under reduced pressure and the N′-hydroxyimidamide was usedin the next step without further purification.

To a solution of 4-phenyl-5-(trifluoromethyl)-2-thiophenecarboxylic acidin 1,4-dioxane were added under nitrogen atmosphere EDCI (125 mg, 0.65mmol) and HOBt (88 mg, 0.65 mmol). The reaction was stirred at roomtemperature for 30 min followed by addition of N′-hydroxyimidamide (114mg, 0.65 mmol), the reaction was stirred for 30 additional minutes atroom temperature followed by 16 h at 95° C. The reaction wasconcentrated under reduced pressure. The crude was diluted with EtOAc(80 mL) and washed with a saturated solution of NaHCO₃ (2×50 ml). Theorganic phase was dried over Na₂SO₄ anhydrous and concentrated underreduced pressure. The product was purified by column chromatographyusing CH₂Cl₂:MeOH (9:1) to yield 91 mg (46.7%) of the product. MS (EI)m/z: 412 (M⁺).

3-(indolin-5-yl)-5-(4-phenyl-5-(trifluoromethyl)thiophen-2-yl)-1,2,4-oxadiazole

To a stirred solution of3-(1H-indol-5-yl)-5-(4-phenyl-5-(trifluoromethyl)thiophen-2-yl)-1,2,4-oxadiazole(40 mg, 0.097 mmol) in acetic acid at 12-14° C. was added slowly sodiumcyanoborohydride (19 mg, 0.29 mmol). At the end of the addition thereaction was allowed to warm to 18-20° C. and was stirred for 2 h. Aftercompletion the reaction mixture was neutralized with 50% sodiumhydroxide and extracted with ethyl acetate (50 ml×2). The organic layerswere combined and dried over Na₂SO₄ and removed under reduced pressure.The crude indoline compound was purified by column chromatography usingCH₂Cl₂/MeOH (9:1) to offer the product in 84.3% yield (33.8 mg, 0.082mmol). MS (EI) m/z: 414 (M⁺)

3-(3-methylpyridin-4-yl)-5-(4-phenyl-5-(trifluoromethyl)thiophen-2-yl)-1,2,4-oxadiazole

Hydroxylamine hydrochloride (23.53 g, 339 mmol) was dissolved in water(120 ml) and potassium bicarbonate (33.9 g, 3339 mmol) was addedcautiously. The mixture was stirred slowly until complete solution. Themixture was added to a solution of 3-methyl isonicotinonitrile (2 g,16.9 mmol) in THF (30 mL) at −25° C. (ice methanol bath) and thereaction was stirred at room temperature for 16 h. The reaction mixturewas extracted with EtOAc (3×100 mL) and the combined organic phases werewashed with brine (80 ml). The organic phase was dried over Na₂SO₄ andconcentrated under reduced pressure. The product was purified by columnchromatography using hexanes/EtOAc (1:1) to yield N′-hydroxyimidamide in47% yield (1.2 g).

To a solution of 4-phenyl-5-(trifluoromethyl)-2-thiophenecarboxylic acid(200 mg, 0.735 mmol) in DMF were added under nitrogen atmosphere EDCI(183 mg, 0.95 mmol) and HOBt (129 mg, 0.95 mmol). The reaction wasstirred at room temperature for 30 min followed by addition ofN′-hydroxyimidamide (143 mg, 0.95 mmol), the reaction was stirred for 30min at room temperature followed by 16 h at 95° C. The reaction wasconcentrated under reduced pressure. The crude was diluted with EtOAc(80 mL) and washed with a saturated solution of NaHCO₃ (2×50 ml). Theorganic phase was dried over Na₂SO₄ and concentrated under reducedpressure. The product was purified by column chromatography usingCH₂Cl₂:MeOH (9:1) to yield 161 mg (56.6%) of the product. MS (EI) m/z:412 (M⁺)

4-(5-(3,4-diethoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-ol

To a stirred suspension of 1-oxo-2,3-dihydro-1H-indene-4-carbonitrile (5g, 31.8 mmol) and silica gel (100 mg) in ethanol (30 mL) at 0° C. wasadded NaBH₄ (400 mg, 10.6 mmol). The reaction was allowed to warm up toroom temperature and stirred for 2 h. The solvent was removed underreduced pressure and the product purified by column chromatography inhexane/EtOAc (5:5) to offer1-hydroxy-2,3-dihydro-1H-indene-4-carbonitrile as white solid in 80%yield (4.04 g, 25.4 mmol). ¹H NMR (300 MHz, CDCl₃): δ 7.62 (d, J=7.5 Hz,1H), 7.54 (d, J=7.8 Hz, 1H), 7.33 (t, J=7.8 Hz, 1H), 5.28 (t, J=6.3 Hz,1H), 3.28-3.18 (m, 1H), 3.02-2.92 (m, 1H), 2.63-2.52 (m, 1H), 2.06-1.99(m, 1H).

To a stirred solution of 1-hydroxy-2,3-dihydro-1H-indene-4-carbonitrile(3 g, 18.86 mmol) in ethanol (100 mL) were added cautiously over aperiod of 16 h under refluxing conditions hydroxylamine hydrochloride(6.55 g, 94.3 mmol) and potassium carbonate (13.03 g, 94.3 mmol) inequal portions. The mixture was cooled to room temperature and the solidwas filtered. The organic solvent was concentrated under reducedpressure and the crude was recrystallized from ethanol to yield 2.5 g(69%) of amidoxime.

In a microwave vial, a stirring solution of 3,4-diethoxybenzoic acid(200 mg, 0.95 mmol) in DMF was treated with HOBt (168 mg, 1.24 mmol) andEDCI (237 mg, 1.24 mmol) at room temperature. The reaction was stirredfor 20 min followed by addition, in a single portion, of amidoxime (238mg, 1.24 mmol). The reaction was stirred for additional 30 min at roomtemperature and then heated to 130° C. for 35 min in the initiator. Thereaction was diluted using a saturated solution of NaCl and extractedwith EtOAc (3×80 ml). The organic phase was dried over Na₂SO₄ anhydrousand concentrated under reduced pressure. The product was purified bycolumn chromatography using CH₂Cl₂:MeOH (9:1) to offer the product as awhite solid in 69% yield (208 mg). ¹H NMR (400 MHz, CDCl₃): δ 8.10 (d,J=7.6, 1H), 7.78 (dd, J1=1.6 Hz, J2=8 Hz, 1H), 7.67 (d, J=1.6 Hz, 1H),7.56 (d, J=7.6 Hz, 1H), 7.39 (t, J=7.6 Hz, 1H), 6.97 (d, J=8.0 Hz, 1H),5.29 (t, J=6.4 Hz, 1H), 4.19 (q, J=7.2 Hz, 2H), 4.18 (q, J=7.2 Hz, 2H),3.51-4.43 (m, 1H), 3.22-3.14 (m, 1H), 2.59-2.51 (m, 1H), 2.04-1.97 (m,1H), 1.5 (t, J=7.2 Hz, 3H), 1.49 (t, J=7.2, 3H); ¹³C NMR (100 MHz,CDCl₃): δ 175.2, 168.9, 152.8, 148.9, 146.6, 143.3, 128.9, 127.4, 127.0,123.8, 122.2, 116.7, 112.7, 112.4, 76.2, 64.9, 64.8, 35.7, 31.5, 14.9,14.8. MS (EI) m/z 367 (M⁺), HRMS (EI) for C₂₁H₂₂N₂O₄ (M⁺): calcd367.1652. found 367.1653.

N1-((4-(5-(3,4-diethoxyphenyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)methyl)-N2,N2-diethylethane-1,2-diamine

To a stirred solution of 2-(hydroxymethyl)isonicotinonitrile (570 mg,4.25 mmol) in ethanol (40 mL) were added cautiously over a period of 16h under refluxing conditions hydroxylamine hydrochloride (1.37 g, 21.25mmol) and sodium carbonate (2.25 g, 21.25 mmol)—in equal portions—. Themixture was cooled to room temperature and the solid was filtered. Theorganic solvent was concentrated under reduced pressure and the crudewas recrystallized from ethanol to yield 600 mg (3.59 mmol, 84%) ofamidoxime.

In a microwave vial, a stirring solution of 3,4-diethoxybenzoic acid(300 mg, 1.43 mmol) in DMF was treated with HOBt (250 mg, 1.85 mmol) andEDCI (354 mg, 1.85 mmol) at room temperature. The reaction was stirredfor 20 min followed by addition, in a single portion, of amidoxime (309mg, 1.85 mmol). The reaction was stirred for additional 30 min at roomtemperature and then heated to 130° C. for 35 min in the initiator. Thereaction was diluted using a saturated solution of NaCl and extractedwith EtOAc (3×80 ml). The organic phase was dried over Na₂SO₄ anhydrousand concentrated under reduced pressure. The product was purified bycolumn chromatography using CH₂Cl₂:MeOH (9:1) to offer(4-(5-(3,4-diethoxyphenyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)methanol asbrown solid in 71% yield (350 mg). ¹H NMR (400 MHz, CDCl₃): δ 8.65 (d,J=4.8 Hz, 1H), 8.00 (s, 1H), 7.86 (d, J=4.8 Hz, 1H), 7.70 (dd, J1=2.0Hz, J2=8.8 Hz, 1H), 7.59 (d, J=2.0, 1H), 6.91 (d, J=8.8 Hz, 1H), 4.85(s, 2H), 4.16 (q, J=7.2 Hz, 2H), 4.13 (q, J=7.2 Hz, 2H), 1.49 (t, J=6.8Hz, 3H), 1.46 (t, J=6.8 Hz, 3H); ¹³C NMR (100 MHz CDCl₃): 176.54,167.22, 153.03, 149.36, 148.91, 135.50, 122.23, 120.11, 118.48, 116.05,112.48, 112.17, 64.90, 64.50, 14.82, 14.73. MS (EI) m/z: 342 (M⁺), HRMS(EI) for C₁₈H₁₉N₃O4

To a stirred solution of pyridinol (20 mg, 0.059 mmol) in DMSO (1 ml)were added sequentially N,N′-dicyclohexylcarbodiimide (36.3 mg, 0.176mmol) and 1.0M anhydrous H₃PO₄ in DMSO (30 μL, 0.03 mmol) and thereaction mixture was stirred 2 h at room temperature. Precipitateddicyclohexylurea was filtered off and washed with ether (10 ml) andwater (10 ml). The aqueous layer was extracted with ether (3×20 ml) andthe organic layer was dried over sodium sulfate and concentrated underreduced pressure. The residue was purified by column chromatographyusing CH₂Cl₂:MeOH (95:5) to yield 15 mg (75%) of pyridinecarboxaldehyde.MS (EI) m/z 340 (M⁺).

To a stirred solution of pyridinecarboxaldehyde (15 mg, 0.044 mmol) indichloroethane were added N¹,N¹-diethylethane-1,2-diamine (19 μl, 0.13mmol) and sodium triacetoxyborohydride (11 mg, 0.05 mmol), the reactionwas stirred for 4 h at room temperature. The mixture was poured unsilica gel and was purified by column chromatography usingCH₂Cl₂:MeOH:Et₃N (90:9.8:0.2) to yield 8 mg (42%) of the product as abrown solid. MS (EI) m/z 440 (M⁺).

2-(4-(5-(3,4-diethoxyphenyl)-1,2,4-oxadiazol-3-yl)indolin-1-yl)ethanol

To a stirred solution of 3,4-diethoxybenzoic acid (400 mg, 1.9 mmol) inDMF were added sequentially HOBt (330 mg, 2.5 mmol) and EDCI (474 mg,2.5 mmol) at room temperature. The reaction was stirred for 20 minfollowed by addition, in a single portion, of theN′-hydroxy-1H-indole-4-carboximidamide (666 mg, 3.8 mmol). The reactionwas stirred for additional 30 min at room temperature then heated at90-95° C. for 14 h. The reaction was cooled to room temperature, dilutedusing a saturated solution of Na₂CO₃ and extracted with EtOAc (100ml×3). The organic phase was dried over Na₂SO₄ anhydrous andconcentrated under reduced pressure. The product was purified by columnchromatography using CH₂Cl₂:MeOH (9:1) to afford compound 110 in 50%yield (331 mg). H¹ NMR (400 MHz, CDCl₃): δ 8.01 (d, J=7.2 Hz, 1H), 7.81(dd, J1=2.0 Hz, J2=8.4 Hz, 1H), 7.52 (s, 1H), 7.52 (d, J=8.0 Hz, 1H),7.34 (s, 1H), 7.28 (t, J=8.0 Hz, 1H), 7.23 (s, 1H), 6.96 (d, J=8.4 Hz,1H), 4.18 (q, J=6.8 Hz, 2H), 4.16 (q, J=6.8 Hz, 2H), 1.47 (t, J=6.8 Hz,3H), 1.46 (t, J=6.8 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃): 175.0, 169.5,152.6, 148.9 (2), 125.7, 122.2, 121.8, 121.7, 121.3, 121.2, 117.0,114.4, 114.3, 112.7, 112.5, 64.97, 64.76, 14.86, 14.78. MS (EI) m/z 350(M⁺), HRMS (EI) for C₂₀H₁₉N₃0₃ (M⁺): calcd 350.1499. found 350.1504.

To a stirred solution of the previous product 110 (260 mg, 0.74 mmol) inacetic acid at 10-15° C. was added slowly sodium cyanoborohydride (140mg, 2.25 mmol). The reaction was allowed to warm to 18-20° C. and wasstirred for 2 h. After completion the reaction mixture was neutralizedwith 50% sodium hydroxide and extracted with ethyl acetate (100 ml×2).The organic layers were combined, dried over Na₂SO₄ and removed underreduced pressure. The crude indoline compound was purified by columnchromatography using CH₂Cl₂/MeOH (9:1) to provide the dihydro compoundin 80.5% yield (211 mg, 0.60 mmol). ¹H NMR (300 MHz, CDCl₃): δ 7.78 (dd,J1=2.1 Hz, J2=8.4 Hz, 1H), 7.68 (d, J=1.8 Hz, 1H), 7.55 (d, J=7.8 Hz,1H), 7.16 (t, J=7.5 Hz, 1H), 6.97 (d, J=7.5 Hz, 1H), 6.76 (d, J=7.5 Hz,1H), 4.21 (q, J=6.9 Hz, 2H), 4.16 (q, J=6.9 Hz, 2H), 3.65 (bs, 2H), 3.46(t, J=8.1 Hz, 2H), 1.52 (t, J=3.1 Hz, 3H), 1.48 (t, J=3.3 Hz, 3H); ¹³CNMR (75 MHz, CDCl₃): δ 175.05, 169.06, 152.62, 148.84, 127.84, 123.67,122.09, 118.90, 116.83, 112.53, 112.32, 111.60, 64.86, 64.67, 47.29,31.41, 14.85, 14.78. MS (EI) m/z 352 (M⁺), HRMS (EI) for C₂₀H₂₁N₃O₃(M⁺): calcd 352.1656. found 352.1660.

To a stirred solution of the previous dihydro product (50 mg, 0.14 mmol)in DMF (3 ml) was added potassium carbonate (118 mg, 0.85 mmol) and2-bromoethanol (20 μl, 0.28 mmol). The reaction was stirred at 60° C.for 48 h. At the end of the reaction the solution was poured into water(50 ml) and the mixture was extracted with EtOAc (3×50 ml). The organicphases were combined, washed with water, dried over sodium sulfate andconcentrated under reduced pressure. The product was purified by columnchromatography using CH₂Cl₂:MeOH (9:1) to yield 35 mg (63%) of theproduct as a brown solid. ¹H NMR (300 MHz, CDCl₃) δ: 7.74 (dd, J1=1.8Hz, J2=8.4 Hz, 1H), 7.61 (d, J=2.1 Hz, 1H), 7.33 (dd, J1=0.6 Hz, J2=7.8Hz, 1H), 7.20 (t, J=5.1 Hz, 1H), 7.17 (d, J=1.8 Hz, 1H), 6.70 (d, J=8.1Hz, 1H), 4.14 (q, J=7.2 Hz, 4H), 3.62 (t, J=6.0 Hz, 2H), 3.55 (t, J=8.7Hz, 2H), 3.28 (t, J=8.1 Hz, 2H), 3.21 (t, J=6.0 Hz, 2H), 1.39 (t, J=1.8Hz, 3H), 1.35 (t, J=1.5 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃): δ 168.67,158.97, 158.46, 153.35, 152.73, 148.72, 129.76, 128.39, 122.19, 117.36,115.89, 113.54, 113.38, 111.94, 64.48, 64.43, 58.90, 53.20, 51.46,29.99, 15.00, 14.90. MS (EI) m/z 396 (M⁺), HRMS (EI) for C₂₂H₂₅N₃O₄(M⁺): calcd 396.1918. found 396.1918.

2-(4-(5-(3,4-diethoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-ylamino)ethanol

To a stirred solution of compound 215 (400 mg, 1.09 mmol) in CH₂Cl₂ wereadded at 0° C. pyridine (89 μl, 1.1 mmol) and thionyl chloride (81 μl,1.1 mmol), the reaction was stirred 1 h at room temperature and themixture was concentrated under reduced pressure. The crude was dilutedin DMF (10 ml) and were added potassium carbonate (290 mg, 2.1 mmol) andethanolamine (128 μl, 2.1 mmol), the reaction was stirred overnight at60° C. The reaction mixture was poured into water (100 ml) and extractedwith EtOAc (100 ml×3). The organic phase was dried over Na₂SO₄ andconcentrated under reduced pressure. The crude was purified by columnchromatography using CH₂Cl₂:MeOH (9:1) to yield 312 mg (70% yield) ofthe product as a white solid. ¹H NMR (500 MHz, CDCl₃): δ 8.12 (d, J=7.5Hz, 1H), 7.79 (dd, J1=2.0 Hz J2=8.5 Hz, 1H), 7.68 (d, J=2.0 Hz, 1H),7.63 (d, J=7.5 Hz, 1H), 7.40-7.37 (m, 1H), 4.49-4.47 (m, 1H), 4.23-4.16(m, 4H), 3.78-3.70 (m, 1H), 3.53-3.46 (m, 1H), 3.29-3.22 (m, 1H),2.96-2.94 (m, 4H), 2.56-2.50 (m, 1H), 2.09-2.03 (m, 1H), 1.52-1.49 (m,6H); ¹³C NMR (125 MHz, CDCl₃): δ 175.03, 168.66, 152.71, 148.87, 143.76,128.71, 127.11, 123.89, 122.04, 116.67, 112.63, 112.49, 104.66, 64.84,64.61, 62.70, 60.34, 47.98, 31.90, 29.69, 14.72, 14.64. MS (EI) m/z 410(M⁺), HRMS (EI) for C₂₃H₂₇N₃O₄ (M⁺): calcd 410.2074. found 410.2077.

N1-(4-(5-(3,4-diethoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-N2,N2-diethylethane-1,2-diamine

To a stirred solution of compound 215 (40 mg, 0.109 mmol) in CH₂Cl₂ wereadded at 0° C. pyridine (9 μl, 1.1 mmol) and thionyl chloride (8 μl, 1.1mmol), the reaction was stirred 1 h at room temperature and concentratedunder reduced pressure. The crude was diluted in DMF (1 ml) and wereadded potassium carbonate (29 mg, 0.21 mmol) andN,N-diethylethylenediamine (30 μl, 0.21 mmol). The reaction was stirredovernight at 60° C. The reaction mixture was poured into water (100 ml)and extracted with EtOAc (20 ml×3). The organic phase was dried overNa₂CO₃ and concentrated under reduced pressure. The crude was purifiedby column chromatography using CH₂Cl₂:MeOH (9:1) to yield 65% (33 mg) ofthe product as a brown solid. MS (EI) m/z 465 (M⁺).

3-(1H-benzo[d]imidazol-5-yl)-5-(4-phenyl-5-(trifluoromethyl)thiophen-2-yl)-1,2,4-oxadiazole

In a microwave vial, a stirring solution of 3,4-diethoxybenzoic acid(100 mg, 0.367 mmol) in DMF was treated with HOBt (64 mg, 0.48 mmol) andEDCI (92 mg, 0.48 mmol) at room temperature. The reaction was stirredfor 20 min followed by addition, in a single portion, ofN′-hydroxy-1H-benzo[d]imidazole-4-carboximidamide (68 mg, 0.367 mmol).The reaction was stirred for additional 30 min at room temperature andthen heated to 130° C. for 35 min in the initiator. The reaction wasdiluted using a saturated solution of NaHCO₃ and extracted with EtOAc(3×80 ml). The organic phase was dried over Na₂SO₄ anhydrous andconcentrated under reduced pressure. The crude was purified by columnchromatography using CH₂Cl₂:MeOH (9:1) to provide a 40% yield (61 mg) ofthe product as brown solid. MS (EI) m/z 413 (M⁺).

3-(3,4-diethoxyphenyl)-5-(pyridin-4-yl)-1,2,4-oxadiazole

In a microwave vial, a stirring solution of isonicotinic acid (200 mg,1.62 mmol) in DMF was treated with HOBt (319 mg, 2.43 mmol) and EDCI(467 mg, 2.43 mmol) at room temperature. The reaction was stirred for 20min followed by addition, in a single portion, of(Z)-3,4-diethoxy-N′-hydroxybenzimidamide (436 mg, 1.94 mmol). Thereaction was stirred for additional 30 min at room temperature and thenheated to 130° C. for 35 min in the initiator. The reaction was dilutedusing a saturated solution of NaHCO₃ and extracted with EtOAc (80 ml×3).The organic phase was dried over Na₂SO₄ anhydrous and concentrated underreduced pressure. The product was purified by column chromatographyusing CH₂Cl₂:MeOH (95:5) to offer the product in 26% yield (131 mg) aspale brown solid. ¹H NMR (300 MHz, CDCl₃): δ 8.85 (d, J=5.4 Hz, 2H),8.02 (d, J=6.0 Hz, 2H), 7.71 (dd, J1=1.8 Hz, J2=8.1 Hz, 1H), 7.62 (d,J=2.1 Hz, 1H), 6.95 (d, J=8.4 Hz, 1H), 4.19 (q, J=6.9 Hz, 2H), 4.14 (q,J=6.9 Hz, 2H), 1.50 (t, J=3.0 Hz, 3H), 1.46 (t, J=3.3 Hz, 3H); ¹³C NMR(75 MHz, CDCl₃): δ 173.54, 16928, 151.64, 151.07, 148.91, 131.37,121.48, 121.15, 118.75, 112.74, 111.82, 64.78, 64.59, 14.87, 14.81. MS(EI) m/z: 312 (M⁺), HRMS (EI) for C₁₇H₁₇N₃O₃ (M⁺): calcd 312.1343. found312.1348.

2-(3,4-diethoxyphenyl)-4-(pyridin-4-yl)oxazole

In a microwave vial were dissolved 2-bromo-1-(pyridin-4-yl)ethanonehydrobromide (134 mg, 0.478 mmol) and 3,4-diethoxybenzamide (100 mg,0.478 mmol) in DMF (5 ml) and the reaction was heated at 170° C. for 40min. The reaction mixture was poured in a saturated solution of NaHCO₃and extracted with EtOAc (50 ml×3). The combined organic phases werewashed with a saturated solution of NaCl (2×30 ml) and concentratedunder reduced pressure. The product was purified by columnchromatography using CH₂Cl₂:MeOH (95:5) to yield 4 mg (2.7%) of theproduct. MS (EI) m/z: 311 (M⁺).

2-(3,4-diethoxyphenyl)-4-phenyloxazole

In a microwave vial were dissolved 2-bromo-1-phenylethanone (95 mg,0.478 mmol) and 3,4-diethoxybenzamide (100 mg, 0.478 mmol) in DMF (5 ml)and the reaction was heated at 170° C. for 40 min. The reaction mixturewas poured in a saturated solution of NaHCO₃ and extracted with EtOAc(50 ml×3). The combined organic phases were washed with a saturatedsolution of NaCl (30 ml×2) and concentrated under reduced pressure. Theproduct was purified by column chromatography using CH₂Cl₂:MeOH (95:5)to yield 25 mg (17%) of the product. MS (EI) m/z: 310 (M⁺)

4-(5-(4-isopropoxy-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-ol

In a microwave vial, a stirring solution of4-isopropoxy-3-(trifluoromethyl)benzoic acid (700 mg, 2.82 mmol) in DMFwas treated with HOBt (495 mg, 3.67 mmol) and EDCI (702 mg, 3.67 mmol)at room temperature. The reaction was stirred for 20 min followed byaddition, in a single portion, ofN′,1-dihydroxy-2,3-dihydro-1H-indene-4-carboximidamide (650 mg, 3.38mmol). The reaction was stirred for additional 30 min at roomtemperature and then heated to 130° C. for 35 min in the initiator. Thereaction was diluted using a saturated solution of NaCl and extractedwith EtOAc (100 ml×3). The organic phase was dried over Na₂SO₄ anhydrousand concentrated under reduced pressure. The product was purified bycolumn chromatography using CH₂Cl₂:MeOH (9:1) to offer the product aswhite solid in 68% yield (780 mg). ¹H NMR (300 MHz, CDCl₃—CH₃OD): δ 8.38(d, J=1.8 Hz, 1H), 8.28 (dd, J1=2.4 Hz, J2=8.7 Hz, 1H), 8.06 (d, J=7.8Hz, 1H), 7.55 (d, J=7.5 1H), 7.7.37 (t, J=7.5 Hz, 1H), 7.11 (dd, J1=2.4Hz, J2=9.0 Hz, 1H), 5.24 (t, J=6.3 Hz, 1H), 4.20 (q, J=6.9 Hz, 1H),3.48-3.40 (m, 1H), 3.19-3.09 (m, 1H), 2.57-2.46 (m, 1H), 2.04-1.92 (m,1H), 1.46 (t, J=6.9 Hz, 3H), 1.39 (d, J=6.0 Hz, 3H); ¹³C NMR (75 MHz,CDCl₃—CH₃OD): δ 169.05, 158.85, 146.82, 143.33, 133.55, 128.79, 127.41,127.22, 116.23, 113.38, 104.88, 65.27, 35.55, 31.44, 21.87, 14.55. MS(EI) m/z 405 (M⁺), HRMS (EI) for C₂₁H₁₉N₂O₃ (M⁺): calcd 405.1420. found405.1424.

4-(5-(4-ethoxy-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-ol

In a microwave vial, a stirring solution of4-ethoxy-3-(trifluoromethyl)benzoic acid (200 mg, 0.85 mmol) in DMF wastreated with HOBt (151 mg, 1.11 mmol) and EDCI (212 mg, 1.11 mmol) atroom temperature. The reaction was stirred for 20 min followed byaddition, in a single portion, ofN′,1-dihydroxy-2,3-dihydro-1H-indene-4-carboximidamide (213 mg, 1.11mmol). The reaction was stirred for additional 30 min at roomtemperature and then heated to 130° C. for 35 min in the initiator. Thereaction was diluted using a saturated solution of NaCl and extractedwith EtOAc (80 ml×3). The organic phase was dried over Na₂SO₄ anhydrousand concentrated under reduced pressure. The product was purified bycolumn chromatography using CH₂Cl₂:MeOH (9:1) to offer the product aswhite solid in 51% yield (200 mg).

¹H NMR (300 MHz, CDCl₃—CH₃OD): δ 8.27 (d, J=1.8 Hz, 1H), 8.21 (dd,J1=2.1 Hz, J2=8.7 Hz, 1H), 7.94 (d, J=7.5 Hz, 1H), 7.44 (d, J=7.8 Hz,1H), 7.26 (q, J=9.9 Hz, 1H), 7.05 (d, J=8.7 Hz, 1H), 5.13 (t, J=6.3 Hz,1H), 4.11 (q, J=6.9 Hz, 2H), 3.38-3.28 (m, 1H), 3.08-2.97 (m, 1H),2.44-2.34 (m, 1H), 1.91-1.84 (m, 1H), 1.35 (t, J=6.9 Hz, 3H); ¹³C NMR(75 MHz, CDCl₃—CH₃OD): δ 150.90, 147.26, 143.96, 137.60, 137.59, 132.62,132.59, 131.31, 131.27, 131.24, 127.21, 120.11, 117.48, 104.99, 79.55,69.27, 39.27, 35.35, 18.39. MS (EI) m/z 391 (M⁺), HRMS (EI) forC₂₀H₁₇F₃N₂O₃ (M⁺): calcd 391.1264. found 391.1261.

4-(5-(4-isopropoxy-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-ol

In a microwave vial, a stirring solution of4-ethoxy-3-(trifluoromethyl)benzoic acid (200 mg, 0.97 mmol) in DMF wastreated with HOBt (172 mg, 1.26 mmol) and EDCI (242 mg, 1.26 mmol) atroom temperature. The reaction was stirred for 20 min followed byaddition, in a single portion, ofN′,1-dihydroxy-2,3-dihydro-1H-indene-4-carboximidamide (243 mg, 1.26mmol). The reaction was stirred for additional 30 min at roomtemperature and then heated to 130° C. for 35 min in the initiator. Thereaction was diluted using a saturated solution of NaCl and extractedwith EtOAc (80 ml×3). The organic phase was dried over Na₂SO₄ anhydrousand concentrated under reduced pressure. The product was purified bycolumn chromatography using CH₂Cl₂:MeOH (9:1) to offer the product aspale yellow solid in 63% yield (229 mg).

¹H NMR (300 MHz, CDCl₃—CH₃OD): δ 8.36 (d, J=2.1 Hz, 1H), 8.29 (dd,J1=2.4 Hz, J2=9.0 Hz, 1H), 8.06 (d, J=7.8 Hz, 1H), 7.55 (d, J=7.5 Hz,1H), 7.37 (t, J=7.5 Hz, 1H), 7.10 (d, J=9.0 Hz, 1H), 5.26 (t, J=6.3 Hz,1H), 4.81-4.73 (m, 1H), 3.48-3.38 (m, 1H), 3.19-3.08 (m, 1H), 2.56-2.49(m, 1H), 2.04-1.95 (m, 1H), 1.45 (d, J=6.3 Hz, 6H); ¹³C NMR (75 MHz,CDCl₃—CH₃OD): δ 173.11, 168.95, 162.82, 146.70, 143.26, 134.15, 134.041,128.27, 127.30, 127.18, 123.18, 116.85, 115.41, 113.66, 103.86, 72.85,35.57, 31.42, 21.82. MS (EI) m/z 362 (M⁺), HRMS (EI) for C₂₁H₁₉N₃O₃(M⁺): calcd 362.1499. found 362.1494.

2-ethoxy-5-(3-(1-hydroxy-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)benzonitrile

In a microwave vial, a stirring solution of 3-cyano-4-ethoxybenzoic acid(200 mg, 1.05 mmol) in DMF was treated with HOBt (185 mg, 1.36 mmol) andEDCI (260 mg, 1.36 mmol) at room temperature. The reaction was stirredfor 20 min followed by addition, in a single portion, ofN′,1-dihydroxy-2,3-dihydro-1H-indene-4-carboximidamide (261 mg, 1.36mmol). The reaction was stirred for additional 30 min at roomtemperature and then heated to 130° C. for 35 min in the initiator. Thereaction was diluted using a saturated solution of NaCl and extractedwith EtOAc (80 ml×3). The organic phase was dried over Na₂SO₄ anhydrousand concentrated under reduced pressure. The product was purified bycolumn chromatography using CH₂Cl₂:MeOH (9:1) to offer the product aspale yellow solid in 79% yield (274 mg).

¹H NMR (300 MHz, CDCl₃—CH₃OD): δ 8.31 (d, J=2.1 Hz, 1H), 8.25 (dd,J1=2.1 Hz, J2=8.7 Hz, 1H), 7.96 (d, J=7.5 Hz, 1H), 7.46 (d, J=7.5 Hz,1H), 7.29 (t, J=7.8 Hz, 1H), 7.06 (d, J=9.0 Hz, 1H), 5.16 (t, J=6.0 Hz,1H), 4.18 (q, J=6.9 Hz, 2H), 3.40-3.30 (m, 1H), 3.10-2.93 (m, 1H),2.46-2.39 (m, 1H), 1.94-1.87 (m, 1H), 1.43 (t, J=6.9 Hz, 3H); ¹³C NMR(75 MHz, CDCl₃—CH₃OD): δ 172.91, 167.05, 161.92, 145.72, 142.08, 133.24,132.83, 127.38, 126.16, 126.10, 121.85, 115.98, 111.76, 101.85, 74.36,64.55, 34.08, 30.18, 13.20. MS (EI) m/z 348 (M⁺), HRMS (EI) forC₂₃H₂₇N₃O₃ (M⁺): calcd 348.1343. found 348.1345.

2-(4-(5-(4-isopropoxy-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-ylamino)ethanol

To a stirred solution of compound 259 (75 mg, 0.185 mmol) in CH₂Cl₂ wereadded at 0° C. pyridine (15 μl, 0.195 mmol) and thionyl chloride (14 μl,0.195 mmol), the reaction was stirred 1 h at room temperature andconcentrated under reduced pressure.

The crude was diluted in DMF (1 ml) and were added DIPEA (161 μl, 0.927mmol) and ethanolamine (56 μl, 0.927 mmol) at 0° C. The reaction wasstirred overnight at 60° C. The reaction mixture was poured into water(100 ml) and extracted with ethyl acetate (20 ml×3). The organic phasewas dried over sodium sulfate and concentrated under reduced pressure.The crude was purified by column chromatography using CH₂Cl₂:MeOH (9:1)to yield 40% (18 mg) of the product as a brown solid.

¹H NMR (300 MHz, CDCl₃—CH₃OD): δ 8.37 (s, 1H), 8.28-8.24 (m, 1H), 8.06(t, J=4.8 Hz, 1H), 7.51 (d, J=6.9 Hz, 1H), 7.35 (t, J=7.5 Hz, 1H), 7.11(d, J=8.4 Hz, 1H), 4.36-4.32 (m, 1H), 4.19 (d, J=6.9 Hz, 1H), 3.67-3.59(m, 3H), 3.39-3.34 (m, 2H), 3.23-3.12 (m, 1H), 2.49-2.43 (m, 1H),1.97-1.90 (m, 1H), 1.45 (t, J=6.9 Hz, 3H), 1.38 (d, J=4.2 Hz, 3H); ¹³CNMR (75 MHz, CDCl₃—CH₃OD): δ 169.63, 146.26, 144.53, 134.30, 128.97,127.76, 127.64, 124.09, 116.72, 115.25, 114.30, 103.98, 72.86, 65.91,63.32, 61.30, 32.74, 32.59, 22.08, 14.76. MS (EI) m/z 448 (M⁺), HRMS(EI) for C₂₃H₂₄F₃N₃O₃ (M⁺): calcd 448.1842. found 448.1849.

2-(4-(5-(4-ethoxy-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-ylamino)ethanol

To a stirred solution of compound 260 (154 mg, 0.394 mmol) in CH₂Cl₂were added at 0° C. pyridine (33 μl, 0.414 mmol) and thionyl chloride(30 μl, 0.414 mmol), the reaction was stirred 1 h at room temperatureand concentrated under reduced pressure. The crude was diluted in DMF (2ml) and were added DIPEA (360 μl, 2.07 mmol) and ethanolamine (125 μl,2.07 mmol) at 0° C. The reaction was stirred overnight at 60° C. Thereaction mixture was poured into water (100 ml) and extracted with ethylacetate (20 ml×3). The organic phase was dried over sodium sulfate andconcentrated under reduced pressure. The crude was purified by columnchromatography using CH₂Cl₂:MeOH (9:1) to yield 18% (31 mg) of theproduct as a brown solid.

¹H NMR (300 MHz, CDCl₃—CH₃OD): δ 8.31 (s, 1H), 8.23 (d, J=8.7 Hz, 1H),7.99 (d, J=7.5 Hz, 1H), 7.48 (d, J=7.2 Hz, 1H), 7.30 (t, J=7.5 Hz, 1H),7.07 (d, J=8.7 Hz, 1H), 4.33 (t, J=6.0 Hz, 1H), 4.15 (q, J=6.9 Hz, 3H),3.64 (t, J=4.5 Hz, 2H), 3.41-3.33 (m, 1H), 3.19-3.08 (m, 1H), 2.78 (t,J=4.8 Hz, 2H), 2.45 (m, 1H), 2.18 (bs, 1H, —NH), 1.96-1.87 (m, 1H), 1.40(t, J=7.2 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃—CH₃OD): δ 168.45, 159.91,144.62, 143.36, 133.04, 128.04, 127.17, 126.73, 126.57, 122.99, 119.63,115.59, 112.89, 100.08, 64.73, 62.19, 60.09, 48.89, 48.32, 31.63, 31.46,13.93. MS (EI) m/z 434 (M⁺), HRMS (EI) for C₂₂H₂₂F₃N₃O₃ (M⁺): calcd434.1686. found 434.1692.

5-(3-(1-(2-hydroxyethylamino)-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile

To a stirred solution of compound 261 (130 mg, 0.360 mmol) in CH₂Cl₂were added at 0° C. pyridine (30 μl, 0.378 mmol) and thionyl chloride(27 μl, 0.378 mmol), the reaction was stirred 1 h at room temperatureand concentrated under reduced pressure. The crude was diluted in DMF (2ml) and were added DIPEA (328 μl, 1.889 mmol) and ethanolamine (114 μl,1.889 mmol) at 0° C. The reaction was stirred overnight at 60° C. Thereaction mixture was poured into water (100 ml) and extracted with ethylacetate (20 ml×3). The organic phase was dried over sodium sulfate andconcentrated under reduced pressure. The crude was purified by columnchromatography using CH₂Cl₂:MeOH (9:1) to yield 23% (34 mg) of theproduct as a pale brown solid.

¹H NMR (300 MHz, CDCl₃—CH₃OD): δ 8.33 (d, J=2.1 Hz, 1H), 8.26 (dd,J1=2.4 Hz, J2=9.0 Hz, 1H), 7.99 (d, J=7.5 (d, J=7.5 Hz, 1H), 7.47 (d,J=7.5 Hz, 1H), 7.33 (t, J=7.5 Hz, 1H), 7.07 (d, J=9.0 Hz, 1H), 4.74 (t,J=6.0 Hz, 1H), 4.27 (t, J=6.6 Hz, 1H), 3.62 (q, J=6.0 Hz, 2H), 3.37-3.32(m, 1H), 3.18-3.10 (m, 1H), 2.79 (t, 5.1 Hz, 2H), 2.48-2.37 (m, 1H),1.92-1.85 (m, 1H), 1.40 (d, J=6.0 Hz, 6H); ¹³C NMR (75 MHz,CDCl₃—CH₃OD): δ 172.73, 168.58, 162.49, 145.45, 143.33, 133.74, 133.71,127.85, 126.69, 126.58, 122.81, 116.40, 115.00, 113.31, 103.33, 72.46,62.30, 60.54, 32.15, 31.51, 21.35. MS (EI) m/z 405 (M⁺), HRMS (EI) forC₂₃H₂₄N₄O₃ (M⁺): calcd 405.1921. found 405.1920.

4-(5-(4-ethoxy-3-nitrophenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-ol

In a microwave vial, a stirring solution of 4-ethoxy-3-nitrobenzoic acid(200 mg, 0.947 mmol) in DMF was treated with HOBt (167 mg, 1.231 mmol)and EDCI (236 mg, 1.231 mmol) at room temperature. The reaction wasstirred for 20 min followed by addition, in a single portion, ofN′,1-dihydroxy-2,3-dihydro-1H-indene-4-carboximidamide (200 mg, 1.04mmol). The reaction was stirred for additional 30 min at roomtemperature and then heated to 130° C. for 35 min in the initiator. Thereaction was diluted using a saturated solution of NaCl and extractedwith EtOAc (80 ml×3). The organic phase was dried over Na₂SO₄ anhydrousand concentrated under reduced pressure. The product was purified bycolumn chromatography using CH₂Cl₂:MeOH (9:1) to offer the product aspale yellow solid in 40% yield (150 mg).

¹H NMR (300 MHz, CDCl₃—CH₃OD): δ 8.03 (d, J=1.2 Hz, 1H), 7.73 (dd,J1=1.5 Hz, J2=8.7 Hz, 1H), 7.46 (d, J=7.5 Hz, 1H), 6.97 (d, J=7.2 Hz,1H), 6.79 (t, J=7.5 Hz, 1H), 6.67 (d, J=8.7 Hz, 1H), 4.65 (t, J=6.0 Hz,1H), 3.70 (q, J=6.9 Hz, 2H), 2.87-2.79 (m, 1H), 2.60-2.49 (m, 1H),1.96-1.90 (m, 1H), 1.43-1.36 (m, 1H), 0.91 (t, J=6.9 Hz, 3H); ¹³C NMR(75 MHz, CDCl₃—CH₃OD): δ 177.85, 168.55, 156.35, 154.87, 146.33, 142.70,139.50, 133.09, 128.02, 126.86, 125.14, 122.43, 115.87, 114.54, 74.97,65.63, 34.68, 30.80, 13.82. MS (EI) m/z 368 (M⁺), HRMS (EI) forC₁₉H₁₇N₃O₅ (M⁺): calcd 368.1241. found 368.1242.

Additional exemplary compounds shown as specific embodiments throughoutbearing compound numbers 1-271 have been prepared and evaluated as shownbelow.

TABLE 1 Biological Data for Selected Compounds Compound Ec₅₀ (S1P₁Ag)Ec₅₀ (S1P₃Ag) Number tPSA ClogP (nM) (nM) 1 55.5 3.99 466 μM  NA 2 46.33.17 6.5 μM NA 3 68.7 1.59 5.9 μM NA 4 58.7 1.86 7.8 μM NA 5 46.3 2.824.1 μM 5100 6 46.3 3.35 4.1 μM NA 7 46.3 3.92 270 nM  782 8 55.5 2.33 73 μM NA 9 55.5 3.78 68.4 μM  NA 10 55.5 3.10 246 nM 3330 11 74 1.506500 NA 12 64.8 2.34 NA NA 14 94.1 5.72 12.3 μM  NA 15 115.7 2.13 19.7μM  NA 16 94.1 4.39 3.3 1201 18 132.5 0.42 397 NA 19 115.7 1.47  12 μMNA 20 118.8 −0.65 NA NA 21 106.5 0.84 NA NA 22 106.5 2.13 1028 NA 2351.1 6.06 3300 3500 24 55.5 2.82 1800 NA 25 71.9 1.24 NA NA 26 96 3.03NA NA 27 55.5 2.47 NA NA 28 55.5 4.07 477 NA 29 55.5 3.58 576 NA 30 64.84.30 1390 NA 31 55.2 3.21 NA NA 32 64.8 3.29 0.15 397 33 64.8 3.30 116NA 34 64.8 3.09 8.8 5370 35 64.8 3.09 3.7 661 36 90.8 2.85 1.7 387 3764.8 2.88 NA NA 38 55.5 2.86 938 NA 39 55.5 2.86 418 NA 40 64.8 3.64 621NA 41 67.9 1.51 7700 NA 42 55.5 2.47 909 NA 43 55.5 3.01 1180 NA 44 55.52.83 731 NA 45 55.5 4.30 1480 NA 46 66.9 4.31 544 NA 47 43.2 298.34 31.8μM  NA 48 58.8 3.44 295 NA 49 46.3 3.67 487 NA 50 64.8 2.57 64 2700 5146.3 4.37 847 NA 52 75.8 2.17 NA NA 53 46.3 5.94 156 327 54 64.8 3.5171.6 322 55 46.3 4.61 113 448 56 46.3 4.91 83.4 NA 57 61.9 1.49 290 NA58 64.8 3.59 11.7 3400 59 46.3 5.06 10.8 5600 60 46.3 5.26 1 803 61 72.34.82 0.78 1319 62 46.3 5.56 5.0  24 μM 63 46.3 5.06 129 NA 64 55.5 3.05228 NA 65 81.6 2.61 319 NA 66 55.5 3.35 1990 NA 67 55.5 2.86 95.5 μM  NA68 46.3 3.87 37.7 NA 69 72.3 3.43 197 NA 70 46.3 4.17 7.08 μM  NA 7146.3 3.67 491.8 NA 72 55.5 3.02 84.8 NA 73 81.6 2.58 249 NA 74 55.5 3.32601 NA 75 55.5 2.83 274 NA 76 46.3 6.49 77 55.6 4.97 450 NA 78 55.6 4.3345.2 NA 79 93.9 4.60 14.9 NA 80 55.6 4.97 86.5 NA 81 55.6 4.33 123 NA 8237.2 6.94 48 NA 86 63.5 6.27 NA NA 87 37.2 4.79 NA NA 88 55.6 2.65 NA NA89 64.8 3.09 224 NA 93 67.6 2.71 2800 NA 100 58.9 4.05 86.3 NA 103 64.82.39 4400 NA 104 46.3 4.05 264 3500 105 46.3 2.26 8400 NA 106 46.3 4.0363 8000 109 46.3 3.18 1500 NA 110 64.4 4.48 0.52 823 121 52.4 5.56 639NA 122 76.2 4.14 5.0 NA 123 64.4 4.39 0.2 529 124 64.4 4.49 3.0 NA 12555.6 5.16 171 NA 128 55.6 4.53 19.1 NA 129 55.6 4.48 4.1 5200 150 64.44.39 4.2 NA 151 55.6 5.06 5.9 2400 152 55.6 5.11 6.0 2100 153 64.4 4.496.9 2000 154 64.4 4.39 3.1 1800 155 81.5 3.28 1.7 NA 165 78.4 3.66 29.4NA 166 52.4 5.14 12.5 NA 167 76.8 3.62 2.2 2200 177 72.6 3.61 0.8 774181 76.8 5.0 733 NA 184 52.4 5.45 11.7 2000 185 52.4 5.86 245 NA 18672.6 3.46 4.2 606 187 72.6 3.46 7 1500 191 55.6 5.27 53.8 NA 192 72.63.69 1.1 691 200 72.6 3.66 104 NA 201 72.6 3.66 0.5 716 202 55.6 5.4135.8 NA 203 55.6 4.78 12.2  10 uM 204 79.7 5.29 32.2 NA 205 61.6 5.65 10 uM NA 206 67.7 4.96 >5000 NA 208 64.8 4.48 153.7 NA 209 85 2.0 0.14938 210 96.2 3.44 163.6 NA 211 52.4 5.67 27.2 13.5 uM 212 52.4 5.67 341NA 213 96.7 3.97 636 NA 214 85 2.06 15.9 13.5 uM 215 72.6 4.6 0.1 NA 21684.7 4.40 91.5 NA 217 55.6 4.75 24.6 13.5 218 97.0 2.58 132 NA 219 64.84.48 13 NA 220 91.1 3.17 28 NA 221 87.9 3.80 1400 NA 222 79.7 4.23 284NA 223 67.7 4.99  10 uM NA 224 79.7 5.29 485 NA 225 85 2.05 24.5 NA 22680.0 3.90 2.7 NA 227 69.5 4.14 21.3 NA 228 75.9 4.03 17.8 2900 229 96.73.26 648 NA 230 87.9 3.70 300 NA 231 87.9 3.70 120 NA 232 58.9 6.24 93.9NA 233 76.5 3.85 581 NA 234 75.9 4.24 <0.5 NA 235 88.2 2.3 82.1 NA 23684.7 3.7 1.1 NA 237 87.9 3.70 1200 NA 238 79.7 5.29 686 NA 239 96.7 3.26867 NA 240 87.9 3.80 3100 NA 241 102.1 3.65 95.6 NA 242 114.1 2.36 26.5NA 243 67.7 5.72 0.7 NA 248 76.8 3.92 1.5 2300 250 75.9 4.03 6.1 NA 25184.7 3.42 3.4 692 252 84.7 3.42 10.1 NA 253 61.6 5.05 26.6 NA 254 76.85.15 15.4 NA 257 64.8 3.09 7.3 258 75.9 4.55 1 NA 259 63.4 4.96 <0.5 NA260 63.4 4.69 <0.5 NA 261 87.2 3.63 <0.5 NA 262 87.2 3.32 <0.5 NA 26375.4 4.81 10 NA 264 75.4 4.50 8 NA 265 99.2 3.44 <0.5 NA 266 64.8 2.33224 NA 267 67.6 2.86 2800 NA 268 52.4 3.42 10.7 NA 269 53.4 3.77 112 NA270 74.8 3.95 2.5 NA 271 86.9 3.77 <0.5 NA

Using the synthetic procedures provided herein, it is within ordinaryskill to prepare any compounds of the invention. Using the knowledge ofthe person of ordinary skill combined with the above cited referencesand methods for evaluation of S1P1 inhibitory bioactivity, the person ofordinary skill in the art can evaluate any compound so prepared for itseffectiveness in inhibiting S1P1, for inhibiting S1P1 selectively in thepresence of other receptor subtypes such as S1P3, and for effectivenessin cell-based bioassays indicative of S1P1 inhibition in vivo.Accordingly, the full scope of the claims provided below are enabled bythe disclosure herein.

REFERENCES

-   1. Matloublan, M.; Lo, C. G; Cinamon, G.; Lesneski, M. J.; Xu, Y.;    Brinkmann, V.; Allende, M. L.; Proia, R. L.; Cyster, J. G. Nature    2004, 427, 355. (b) Allande, M. L.; Dreier, J. L.; Mandala, S.;    Proia, R. L. J. Biol. Chem. 2004, 279, 15396.-   2. Germana, S. M.; Liao, J.; Jo, E.; Alfonso, C.; Ahn, M.-Y.;    Peterson, M. S.; Webb, B.; Lefebvre, S.; Chun, J.; Gray, N.;    Rosen, H. J. Biol. Chem. 2004, 279, 13839.-   3. (a) Budde, K.; Schmouder, R. L.; Nashan, B.; Brunkhorst, R.;    Lucker, P. W.; Mayer, T.; Brookman, L.; Nedelman, J.; Skerjanec, A.;    Bohler, T.; Neumayer, H.-H. Am. J. Transplant. 2003, 3, 846-854. (b)    Budde, K.; Schmouder, R. L.; Brunkhorst, R.; Nashan, B.; Lucker, P.    W.; Mayer, T.; Choudhury, S.; Skerjanec, A.; Kraus, G.;    Neumayer, H. H. J. Am. Soc. Nephrol. 2002, 13, 1073-1083. (c)    Kahan, B. D.; Karlix, J. L.; Ferguson, R. M.; Leichtman, A. B.;    Mulgaonkar, S.; Gonwa, T. A.; Skerjanec, A.; Schmouder, R. L.;    Chodoff, L. Transplantation 2003, 7, 1079-1084.-   4. Yan L.; Huo P.; Hale J.; Mills S. G.; Hajdu R.; Keohane C. A.;    Rosenbach M. J.; Milligan J. A.; Shei G.; Chrebet G.; Bergstrom J.;    Card D.; Mandala S. M. Bioorg Med Chem Lett 2006, 16, 3684-3687.-   5. Li Z.; Chen W.; Hale J.; Lynch C. L.; Mills S. G.; Hajdu R.;    Keohane C. A.; Rosenbach M. J.; Milligan J. A.; Shei G.; Chrebet G.;    Parent S. A.; Bergstrom J.; Card D.; Forrest M.; Quackenbush E. J.;    Wickham L. A.; Vargas H.; Evans R. M.; Rosen H.; Mandala S. J Med    Chem 2005, 48, 6169-6173.-   6. Hale J. J.; Lynch C. L.; Neway W.; Mills S. G.; Hajdu R.;    Keohane C. A.; Rosenbach M. J.; Milligan J. A.; Shei G.; Parent S.    A.; Chrebet G.; Bergstrom J.; Card D.; Ferrer M.; Hodder P.;    Strulovici B.; Rosen H.; Mandala S. J Med Chem 2004, 47, 6662-5.-   7. Gonzalez-Cabrera, P. J., T. Hla, et al. (2007). “Mapping pathways    downstream of sphingosine 1-phosphate subtype 1 by differential    chemical perturbation and proteomics.” J Biol Chem 282(10): 7254-64.-   8. Jo, E., M. G. Sanna, et al. (2005). “S1P1-selective in    vivo-active agonists from high-throughput screening: off-the-shelf    chemical probes of receptor interactions, signaling, and fate.” Chem    Biol 12(6): 703-15.-   9. Wei, S. H., H. Rosen, et al. (2005). “Sphingosine 1-phosphate    type 1 receptor agonism inhibits transendothelial migration of    medullary T cells to lymphatic sinuses.” Nat Immunol 6(12): 1228-35.

What is claimed is:
 1. A method of treatment of a malcondition in a patient having such malcondition, wherein the malcondition is multiple sclerosis, transplant rejection or adult respiratory distress syndrome, comprising administering to the patient an effective dose of a compound of formula (I), or a pharmaceutically acceptable salt, tautomer, or stereoisomer, thereof:

wherein a dashed line signifies that a single bond or a double bond can be present, provided that there are two double bonds and three single bonds in the ring comprising A¹, A², and A³; A¹ and A³ are N and A² is O; L¹ and L² are each independently a bond; J independently at each occurrence is F, Cl, Br, I, OR′, OC(O)N(R′)₂, CN, CF₃, OCF₃, R′, methylenedioxy, ethylenedioxy, N(R′)₂, SR′, SOR′, SO₂R′, SO₂N(R′)₂, SO₃R′, C(O)R′, C(O)C(O)R′, C(O)CH₂C(O)R′, C(S)R′, C(O)OR′, OC(O)R′, OC(O)OR′, C(O)N(R′)₂, OC(O)N(R′)₂, C(S)N(R′)₂, (CH₂)₀₋₂NHC(O)R′, N(R′)N(R′)C(O)R′, N(R′)N(R′)C(O)OR′, N(R′)N(R′)CON(R′)₂, N(R′)SO₂R′, N(R′)SO₂N(R′)₂, N(R′)C(O)OR′, N(R′)C(O)R′, N(R′)C(S)R′, N(R′)C(O)N(R′)₂, N(R′)C(S)N(R′)₂, N(COR′)COR′, N(OR′)R′, C(═NH)N(R′)₂, C(O)N(OR′)R′, or C(═NOR′)R′, wherein R′ is independently at each occurrence hydrogen or an alkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl wherein any alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl is substituted with 0-3 J; R⁵ a group of formula a-i

mono- or pluri-substituted with J, wherein a wavy line indicates a point of attachment; R⁶ is phenyl mono- or pluri-substituted with J.
 2. The method of claim 1 wherein the malcondition is transplant rejection or adult respiratory distress syndrome.
 3. The method of claim 1 wherein the malcondition is multiple sclerosis. 